ART: The New, The Old and The Ugly

ART: The New, The Old and The Ugly

Our Current ARVS The Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs/ NtRTIs) Abacavir Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine The Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs ) Efavirenz Nevirapine Triomune, Atripla, Triplavar The Protease Inhibitors (PIs) Atazanavir Darunavir Lopinavir Ritonavir Fixed-drug combinations Combivir, Kivexa, Truvada

ARVS REGISTSERED IN SOUTH AFRICA The Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs/ NtRTIs) Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Fixed-drug combinations Combivir, Kivexa, Truvada The Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz Nevirapine Etravirine Rilpivirine Triomune, Atripla, Tripalvar, Complera The Integrase Inhibitors (ISTIs) Raltegravir The Protease Inhibitors (PIs) Amprenavir Atazanavir Darunavir Indinavir Lopinavir Ritonavir Saquinavir

THE ANTIRETROVIRAL DRUGS The Nucleoside/ Nucleotide Reverse Transcriptase Inhibitors (NRTIs/ NtRTIs) Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Fixed-drug combinations Combivir, Kivexa, Truvada The Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs ) Efavirenz Nevirapine Etravirine Rilpivirine Triomune, Atripla, Complera The Integrase Inhibitors (ISTIs) Raltegravir Elvitegravir Dolutegravir The QUAD The Protease Inhibitors (PIs) Amprenavir Atazanavir Darunavir Indinavir Lopinavir Ritonavir Saquinavir Tipranavir

Drugs to be covered Etravirine Rilpivirine Raltegravir Elvitegravir Dolutegravir Darunavir/r Maraviroc

Etravirine Etravirine (ETV) is a second generation NNRTI that ETV works like other NNRTIs by binding to the catalytic site of the RT enzyme Active against HIV with K103N and Y181C This potency appears to be related to etravirine's flexibility as a molecule Dosage 200mg bd

Etravirine (2) Pivotal study DUET 1 and 2 OBR +darunavir/r +etravirine/placebo After 24 weeks, pooled analysis -etravirine study arm achieved an undetectable viral load (58.9% vs 41.1%; p<0.0001). There was also a significantly greater increase in CD4 cell count from baseline in the etravirine arm (86 vs 67 cells/mm3; p<0.006).

Summary of Study Design DUET 1 and 2 Week 24 Week 48 HIV-infected patients with virologic failure on current HAART regimen, history of 1 NNRTI RAM, 3 primary PI mutations, and HIV-1 RNA > 5000 copies/ml (DUET-1: N = 612; DUET-2: N = 591) Etravirine 200 mg BID + Darunavir/Ritonavir-containing OBR* (DUET-1: n = 304; DUET-2: n = 295) Placebo + Darunavir/Ritonavir-containing OBR* (DUET-1: n = 308; DUET-2: n = 296) *Investigator-selected OBR included darunavir/ritonavir 600/100 mg twice daily + 2 NRTIs ± enfuvirtide. 1. Madruga JV, et al. Lancet. 2007;370:29-38. 2. Lazzarin A, et al. Lancet. 2007;370:39-48.

Main Findings Significantly more patients achieved HIV-1 RNA < 50 copies/ml with etravirine vs placebo HIV-1 RNA reduction from baseline greater in etravirine arms than placebo arms Etravirine treatment resulted in greater CD4+ cell count increases from baseline compared with placebo (statistical significance reached in DUET-1 only) Madruga JV, et al. Lancet. 2007;370:29-38. Lazzarin A, et al. Lancet. 2007;370:39-48.

13 RT mutations at eight positions were found to reduce ETV activity V90I, A98G, L100I, K101E/P, V106I, V179D/F, Y181C/I/V and G190A/S

Etravirine

Etravirine FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly NO NO YES? NO UNK

Rilpivirine

Rilpivirine Novel NNRTI Single day dosage Co-formulated with TDF and FTC as Complera

ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients Randomized, double-blind phase III trials Stratification by BL HIV-1 RNA < 100,000 vs 100,000 copies/ml, NRTI use* Wk 48 primary analysis Wk 96 final analysis ECHO (N = 690) Treatment-naive, HIV-1 RNA 5000 copies/ml no NNRTI RAMs, susceptible to NRTIs THRIVE (N = 678) Rilpivirine 25 mg QD + TDF/FTC 300/200 mg QD (n = 346) EFV 600 mg QD + TDF/FTC 300/200 mg QD (n = 344) Rilpivirine 25 mg QD + 2 NRTIs (n = 340) EFV 600 mg QD + 2 NRTIs (n = 338) *THRIVE only. Selected by investigator from ABC/3TC, TDF/FTC, ZDV/3TC. Cohen C, et al. AIDS 2010. Abstract THLBB206.

ECHO, THRIVE: Rilpivirine vs EFV in Treatment-Naive Patients Patients (%) 100 80 60 40 20 0 n = Rilpivirine EFV HIV-1 RNA < 50 copies/ml (ITT-TLOVR) at Wk 48 84.3 686 82.3 682 Pooled ECHO *P <.0001 for noninferiority at -12% margin. 85.6 82.9 82.8 81.7 346 THRIVE Cohen C, et al. AIDS 2010. Abstract THLBB206. Graphics used with permission. 344 340 338 Patients (%) Patients (%) HIV-1 RNA < 50 copies/ml at Wk 48 by BL VL 6.6 (1.6-11.5) 100 90 90 91 84 83 84 80 60 40 20 0 100 80 60 40 20 0 332/ 368 Pooled ECHO THRIVE 100,000 copies/ml -3.6(-9.8 to +2.5) 77 246/ 318 276/ 330 81 285/ 352 162/ 181 76 82 125/ 165 136/ 163 149/ 181 170/ 187 79 80 121/ 153 140/ 167 136/ 171 Pooled ECHO THRIVE > 100,000 copies/ml

ECHO, THRIVE: Treatment Failure, Resistance, and Adverse Events Patients (%) Treatment Failure in ECHO and THRIVE 15 Rilpivirine 12 9 6 3 0 9.0 n = 346 686 Resistance at Virologic Failure Wk 48 Outcome VF 4.8 682 2.0 686 AE 6.7 682 Rilpivirine (n = 686) EFV Efavirenz (n = 682) Adverse Events and Discontinuation Wk 48 Outcome, % Rilpivirine (n = 686) Efavirenz (n = 682) P Value DC for AE 3 8.0005 Most Common AEs of Interest, % Any neurologic AE 17 38 <.0001 Any psychiatric AE 15 23.0002 Any rash 3 14 <.0001 VF with resistance data, n 62 28 No NNRTI or NRTI RAMs,% 29 43 1 Emergent NNRTI RAM,% 63 54 Most frequent NNRTI RAM E138K K103N 1 Emergent NRTI RAMs, % 68 32 Most frequent NRTI RAM M184I M184V Cohen C, et al. AIDS 2010. Abstract THLBB206. Table used with permission.

Rilpivirine FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly YES YES YES NO NO UNK

Raltegravir Novel mode of action Acts on intergrase as an inhibitor 400mg bd

HIV Replication Cycle and Drug Targets a. Entry inhibitors b. Reverse transcriptase inhibitors c. Protease inhibitors d. 3 -processing inhibitors e. Strand transfer inhibitors Pommier Y, et al. Nat Rev Drug Discov. 2005;4:236-248.

BENCHMRK-1 & -2: Patients With HIV-1 RNA < 50 c/ml at Week 48 RAL + OBR BENCHMRK-1 [1] BENCHMRK-2 [2] Placebo + OBR 100 100 Patients (%) 80 60 40 20 0 0 2 4 62%* 65%* 33% 31% 8 12 16 24 32 40 48 Weeks Patients (%) 80 60 40 20 0 0 2 4 62%* 36% 60%* 34% 8 12 16 24 32 40 48 Weeks n = n = 232 231 231 230 229 232 229 118 118 118 118 117 118 118 230 118 231 118 230 228 227 230 229 229 224 119 119 118 119 119 119 119 *P <.001 for RAL vs placebo, derived from a logistic regression model adjusted for baseline HIV-1 RNA level (log 10 ), first ENF use in OBR, first DRV use in OBR, active PI in OBR. 228 119 228 119 1. Cooper DA, et al. CROI 2008. Abstract 788. 2. Steigbigel R, et al. CROI 2008. Abstract 789. Adapted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA, Copyright 2008 Merck & Co., Inc. All Rights Reserved.

STARTMRK: Efavirenz vs Raltegravir at 156 Wks in Antiretroviral-Naive Phase III trial of EFV vs RAL, both with TDF/FTC in tx-naive patients At Wk 156, RAL noninferior to EFV (ITT, NC = F analysis) HIV-1 RNA < 50 c/ml (%) 100 80 60 40 20 0 0 16 32 48 60 72 84 96 108 120 132 144 156 Patients at Risk, n RAL EFV 281 282 278 280 86 82 281 282 Wks 280 281 281 279 CD4+ count : +332 (RAL) vs +295 (EFV) Lazzarin A, et al. ICAAC 2011. Abstract H2-790. 81 79 (95% CI) = +7.3 (-0.2 to +14.7) Noninferiority P <.001 279 281 Patients 75 68 281 282 RAL EFV HIV-1 RNA < 50 c/ml by Prespecified BL Characteristic* Subgroup, n/n (%) RAL EFV Male Female Black White Latino VL 100K VL > 100K CD4 50 CD4 > 50-200 CD4 > 200 HBV ± HCV No coinfection Age median Age > median 172/194 (89) 40/43 (93) 18/23 (78) 83/94 (88) 50/54 (93) 99/105 (94) 113/132 (86) 16/23 (70) 80/89 (90) 116/125 (93) 11/12 (92) 201/225 (89) 109/124 (88) 103/113 (91) 159/188 (85) 33/39 (85) 17/22 (77) 82/90 (91) 42/55 (76) 93/111 (84) 99/116 (85) 24/28 (86) 68/84 (81) 100/115 (87) 11/13 (85) 181/214 (85) 108/131 (82) 84/96 (88) *Study not powered for statistical significance for these comparisons.

REALMRK: 48-Wk Efficacy of Raltegravir BID in Women, Blacks Multicenter, multinational, open-label, single-arm study to determine efficacy of RAL 400 mg BID (+ investigator-selected ARVs) in women, blacks populations underrepresented in clinical trials Enrollment goals: 25% women (actual 47%), 50% black (actual 74%) No difference in PK parameters by race or sex; no new RAL safety signals noted Retention 84% throughout study; bolstered by strict selection criteria and retention initiatives Male Female Black Nonblack HIV-1 RNA < 50 copies/ml at Wk 48 (%) 100 80 60 40 20 71.4 85.7 Naive 0 Squires K, et al. ICAAC 2011. Abstract H2-789. Failure Previously Treated 78.6 71.4 66.0 61.4 63.8 64.0 80.5 Intolerant 71.8 69.4 10/14 6/7 11/14 5/7 33/50 27/44 44/69 16/25 33/41 28/39 43/62 18/18 100

ANRS REFLATE: EFV-vs RAL-Based ART in HIV/TB-Coinfected Pts Multicenter, randomized, open-label phase II trial Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 24 Wk 24 Primary endpoint Wk 48 Antiretroviral-naive pts initiating rifampincontaining therapy* for TB coinfection (N = 154) Raltegravir 800 mg BID + Tenofovir + Lamivudine (n = 51) Raltegravir 400 mg BID + Tenofovir + Lamivudine (n = 51) Efavirenz + Tenofovir + Lamivudine (n = 52) Raltegravir 400 mg BID + Tenofovir + Lamivudine *Rifampin-containing therapy initiated before ART and consisted of rifampin, isoniazid, pyrazinamide, and ethambutol for 2 mos, followed by rifampin and isoniazid for 4 mos. Grinsztejn B, et al. AIDS 2012. Abstract THLBB01.

REFLATE: Virologic Suppression at Wk 24 by ART Regimen 100 RAL 400 mg RAL 800 mg EFV Pts with VL < 50 c/ml (%) 80 60 40 20 Virologic Failure at Wk 24 ITT; M = F, D/C = F RAL 400 (n = 51) 78 76 67 RAL 800 (n = 51) EFV (n = 51) VL > 50 c/ml, n (%) 12 (24) 4 (8) 15 (29) 0 0 2 4 8 12 16 20 24 Wks Grinsztejn B, et al. AIDS 2012. Abstract THLBB01. Graphic reproduced with permission.

Raltegravir FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly NO NO YES NO MAYBE UNK

Elvitegravir Intergrase inhibitors. Requires boosting ritonavir Cobicistat Co-formulated with a booster, TDF and FTC QUAD-Stribild

Cobicistat: A New Boosting Agent Small molecule with no HIV activity No concern of drug resistance in pts with suboptimal virologic response Similar from BL in fasting TC and TGs compared with RTV when boosting same agent [1] Inhibitor of CYP3A4; many drug drug interactions [2,3] Modest, rapid increase in serum Cr due to inhibition of tubular secretion [3] Not associated with any change in actual GFR Other drugs (including ARVs) have similar effect [4,5] Availability of cobicistat has allowed for development of new coformulated agents and regimens 1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. DHHS Guidelines February 2013. 3. TDF/FTC/EVG/COBI [package insert]. 4. RPV [package insert]. 5. DTG [package insert].

Renal Monitoring With Cobicistat At BL,* Estimated CrCl Urine glucose Urine protein Change From BL in Serum Cr (mg/dl; IQR) 0.20 0.15 0.10 0.05 0-0.05-0.10 BL Wk 4 new baseline against which further changes should be measured 2 4 8 12 16 24 32 40 48 Wks *Serum phosphorus should be measured in patients at risk for renal impairment 9. TDF/FTC/EVG/COBI[package insert]. 10. DHHS Guidelines February 2013.

Renal Monitoring With Cobicistat At BL,* Estimated CrCl Urine glucose Urine protein Serum Cr* Serum Cr* UA Serum Cr* Serum Cr* UA Change From BL in Serum Cr (mg/dl; IQR) 0.20 0.15 0.10 0.05 0-0.05-0.10 BL Wk 4 new baseline against which further changes should be measured 2 4 8 12 16 24 32 40 48 Wks *Serum phosphorus should be measured in patients at risk for renal impairment Coformulated drugs containing COBI should not be initiated in pts with estimated CrCl < 70 ml/min Studies ongoing in pts with CrCl < 70 Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF TDF/FTC/EVG/COBI should not be used with other nephrotoxic drugs 12. TDF/FTC/EVG/COBI[package insert]. 13. DHHS Guidelines February 2013.

Key Drug Drug Interactions With COBI Antacids Benzodiazepines Beta-blockers Calcium channel blockers Erectile dysfunction drugs Inhaled/injectable corticosteroids MVC OCPs (norgestimate) Rifampin Statins 14. DHHS Adult Guidelines. February 2013

Cobicistat Status in EU and US In July 2013, EMEA approved cobicistat as a PK enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of a complete ART regimen in adults In US, currently approved only as part of coformulated single-tablet regimen TDF/FTC/EVG/COBI Approval as single agent pending 15. EMA.europa.eu. Assessment report on cobicistat. 16. FDA.gov. Approval of TDF/FTC/EVG/COBI.

Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Patients Randomized, double-blind, active-controlled phase III studies Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 Study 102 [17] (N = 700) Treatment naive HIV-1 RNA 5000 copies/ml Any CD4+ cell count Susceptible to TDF, FTC, and EFV, or ATV egfr 70 ml/min Study 103 [18] (N = 708) EVG/COBI/TDF/FTC QD (n = 348) EFV/FTC/TDF QD (n = 352) EVG/COBI/TDF/FTC QD (n = 353) ATV/RTV + TDF/FTC QD (n = 355) 17. Sax P, et al. Lancet. 2012;379:2439-2448. 18. DeJesus E, et al. Lancet. 2012;379:2429-2438.

EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk 144 100 EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) 95% CI for Difference 80 88 84 8482 80 75 Favors EFV Favors EVG/COBI Subjects (%) 60 40 Wk 48 [1] Wk 96 [2] 3.6% -1.6% 2.7% -2.9% 8.8% 20 7 7 6 8 7 10 4 5 5 7 6 7 Wk 144 [3] 4.9% -1.3% 11.1% 0 Wk 48 Wk 96 Wk 144 Wk 48 Wk 96 Wk 144 Wk 48 Wk 96 Wk 144-12% 12% 0 Virologic Success* Virologic Failure D/c due to AEs *HIV-1 RNA < 50 copies/ml as defined by FDA Snapshot algorithm. 19. Sax PE, et al. Lancet. 2012;379:2439-2448. 20. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 21. Wohl D, et al. ICAAC 2013. Abstract H-672a.

EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144 100 80 90 87 83 82 78 75 EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) 95% CI for Difference Favors ATV/RTV Favors EVG/COBI Subjects (%) 60 40 20 0 Wk 48 Wk 96 Wk 144 Virologic Success* 5 5 7 7 8 7 4 Wk 48 Wk 96 Wk 144 Virologic Failure *HIV-1 RNA < 50 copies/ml as defined by FDA Snapshot algorithm. Wk 48 5 4 6 6 8 22. De Jesus E, et al. Lancet. 2012;379:2429-2438. 23. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 24. Clumeck N, et al. EACS 2013. Abstract LBPS7/2. Wk 96 Wk 144 D/c due to AEs Wk 48 [22] Wk 96 [23] -2.1% -4.5% Wk 144 [24] 2.7% 1.1% 3.1% 7.5% 6.7% -3.2% 9.4% -12% 12% 0

QUAD FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly YES YES YES YES NO UNK

Dolutegravir Dolutegravir (DTG) is a newer, potent INSI with low nanomolar activity that is suitable for once-daily, unboosted dosing Furthermore, in vitro, DTG retains activity against most isolates carrying major integrase resistance mutations to RAL and/or EVG

Dolutegravir Phase III Trials in Treatment-Naive Patients Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 copies/ml at Wk 48 SPRING-2 [30] (active controlled, double blind) ART-naive pts VL 1000 c/ml (N = 822) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) VL < 50 at Wk 48 88 86 85 VL < 50: DTG/ABC/3TC SINGLE [31] (active controlled, double blind) ART-naive pts VL 1000 c/ml HLA-B*5701 neg CrCl > 50 ml/min (N = 833) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) 88 88 81 FLAMINGO [32] (open label) ART-naive pts VL 1000 c/ml (N = 484) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) 90 90 83 *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 30. Raffi F, et al. Lancet. 2013;381:735-743. 31. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818. 32. Feinberg J, et al. ICAAC 2013. Abstract H1464a..

Resistance on SPRING 1 Samples from participants meeting Protocol defined Virological failure criteria were sent for resistance testing. No participants on DTG have had emergence of a virus with an INI resistance mutation. One participant receiving DTG 10mg developed virus with the mutation M184M/V in reverse transcriptase.

SINGLE No treatment-emergent genotypic resistance that resulted in reduced susceptibility to either DLG or the background regimen was seen in the DLG arm in SINGLE.

OF course the ever present TB and pregnancy question Increase the dose of DLG-poor evidence Category B drug.

DLV/ABC and TDF In treatment-naive HIV-infected patients starting initial ART, dolutegravir(dtg) plus abacavir (ABV)/lamivudine (3TC) maintained superiority over efavirenz (EFV)/tenofovir DF (TDF)/emtricitabine (FTC) at Week 96 DTG arm associated with higher virologic response rate, primarily due to lower rate of discontinuations related to tolerability DTG arm associated with more favorablesafety profile vscontrol arm, with lower rates of central nervous system (CNS) events, rash, and liver function test elevations No major treatment-emergent mutations conferring INSTI or NRTI resistance detected through 96 weeks in DTGtreated patients

Dolutegravir FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly YES YES YES YEs NO UNK

Darunavir dosing summary Darunavir/r dosing is determined by treatment experience and presence or absence of darunavir mutations on genotypic lab analysis.

Treatment-experienced patients POWER 1 compared the efficacy and safety of four doses of DRV (TMC114) plus 100 mg RTV with investigator-selected control protease inhibitors (CPIs) 63% of the patients were resistant to all commercially available PI. Virologic and immunologic outcomes were significantly better in the DRV/r arms compared to the CPI arm. In the 600 mg DRV twice daily arm, mean CD4 gains were as high as 124 cells at 24 weeks and 53 percent attained an HIV RNA level <50 copies/ml;

Treatment-experienced patients POWER 3 DRV/r plus optimized background therapy. No comparator arm was used. Of 324 patients who were treated for 48 weeks, 45 percent achieved HIV RNA reductions to <50 copies/ml.

Treatment-experienced patients Treatment-experienced patients with recent genotypic testing demonstrating theabsence ofdarunavir-associated mutations: darunavir (800 mg) once daily plus ritonavir (100 mg) once daily.the relevant darunavir mutations include:v11i, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V.

Treatment-experienced patients POWER 1 and POWER 2 were randomized, multinational, phase IIB trials, which compared DRV co-administered with low-dose RTV to other PIs in a population of highly treatment-experienced patients

Treatment-experienced patients Darunavir-associated mutations on genotype: darunavir (600 mg; given as one tablet) twice daily plus ritonavir (100 mg) twice daily. The relevant darunavir mutations include: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V.

Treatment-naïve patients Darunavir (800 mg) once daily plus ritonavir (100 mg) once daily ARTEMIS: randomized, open-label, phase 3 non-inferiority trial compared the safety and efficacy of DRV/r (800/100 mg once daily) with LPV/r in 689 treatment-naive patients

Treatment-naïve patients At week 48, DRV/r was found to be noninferior to LPV/r; viral suppression was achieved in 84 versus 78 percent, respectively. At 96 weeks, significantly more patients in the DRV/r arm achieved viral suppression than in the LPV/r arm (79 versus 71 percent) Both treatments were well tolerated.

Darunavir FDC Single day dosage Low side effect profile High barrier to resistance TB friendly Pregnancy friendly NO MAYBE YES YES NO UNK

Third line Peer Revivew committee Third line drugs now on tender Centrally procured Receive motivation Screen Add to database Send to Virtual Committee Committee recommendation to motivator and CPU Update database

Third line committee 130 patients on the database. 115 have already been reviewed. (5 motivations no GT results) Number of motivations declined 12 Number of patients on third line treatment 98