HIV Treatment: New and Veteran Drugs Classes

HIV Treatment: New and Veteran Drugs Classes Jonathan M Schapiro, MD National Hemophilia Center Stanford University School of Medicine Rome, March 2013

Overview Many excellent antiretroviral agents are available in resource rich settings to treat HIV infected patients These include agents for older and newer drug classes An intimate knowledge of the characteristic of each class and individual drug is crucial for optimal therapeutic decision making Key virological and pharmacological drug characteristics often dictate how these drugs are best chosen and combined

What are the Barriers to Successful Antiretroviral Therapy?

Characteristics of Antiretroviral Drugs Drug Virus Adherence Pharmacology Potency/Resistant Dosing schedule Adverse events Absorption/metabolism Drug interactions Mechanism of action Concentration Viral mutations

Goals for Successful Antiretroviral Therapy Continued suppression of viral replication No or minimal toxicity and adverse events Convenient with no or minimal reduction in quality of life Priority

HIV Drug Targets RNA RT RNA DNA RT DNA DNA RNA RNA Provirus Proteins

NRTI NRTI RNA RT RNA DNA RT DNA DNA RNA RNA Provirus Proteins

NRTI Tenofovir (TDF) Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Zidovudine (AZT, ZDV) Didanosine (ddi) Stavudine (D4T)

NRTI Tenofovir (TDF) Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Zidovudine (AZT, ZDV) Didanosine (ddi) - Rarely used due to increased toxicity Stavudine (D4T) Rarely used due to increased toxicity

NRTI Tenofovir (TDF) Abacavir (ABC) Emtricitabine (FTC) Lamivudine (3TC) Zidovudine (AZT, ZDV)

Cross Resistance Among NRTI Stanford HIV Drug Resistance Database, Robert Shafer PI, January 2012

HIV Drug Targets NNRTI RNA RT RNA DNA RT DNA DNA RNA RNA Provirus Proteins

NNRTI Efavirenz (EFV) Nevirapine (NVP) Etravirine (ETV) Rilpivirine (RPV)

Structures of NNRTIs Nevirapine Efavirenz TMC12

Cross Resistance Among NNRTI Stanford HIV Drug Resistance Database, Robert Shafer PI, January 2012

Resistance to Nevirapine with Single Mutation Increased Fold Change to NVP with Mutation K103N Stanford Resistance Database, Dec 2010

Resistance to Efavirenz with Single Mutation Increased Fold Change to EFV with Mutation K103N Stanford Resistance Database, Dec 2010

Structures of NNRTIs Nevirapine Efavirenz Etravirine

DUET-1 and DUET-2: DRV/r + TMC125 + OBR in Highly Treatment Experienced Patients Screening 6 weeks 600 patients target per trial 48-week treatment period with optional 48-week extension 24-week primary analysis TMC125 + BR* (including DRV/r) Placebo + BR* (including DRV/r) *BR = DRV/r with optimised NRTIs and optional enfuvirtide Follow up 4 weeks Viral load >5,000 HIV-1 RNA copies/ml and stable therapy for 8 weeks 1 NNRTI MU, at screening or in documented historical genotype 3 primary PI mutations at screening Primary endpoint was the proportion of patients achieving viral load <50 HIV-1 RNA copies/ml when all patients had reached Week 24 or discontinued

Patients with viral load <50 copies at Week 24 DUET-1 DUET-2 Responders (%) + 95% CI 100 80 60 40 20 TMC125 + BR (n=304) Placebo + BR (n=308) p=0.0050 56% 39% Responders (%) + 95% CI 100 80 60 40 20 TMC125 + BR (n=295) Placebo + BR (n=296) p=0.0003 62% 44% 0 0 4 8 12 16 20 24 Time (weeks) 0 0 4 8 12 16 20 24 Time (weeks) CI = confidence interval; intent-to-treat (ITT) population; TLOVR = time to loss of virological response imputation algorithm

ETR Weighted Score Mutations have accumulative effect Impact on virological response relative to weight of mutation Mutation Weight Y181I 3 Y181V 3 K101P 2.5 L100I 2.5 Y181C 2.5 M230L 2.5 E138A 1.5 V106I 1.5 G190S 1.5 V179F 1.5 V90I 1 V179D 1 K101E 1 K101H 1 A98G 1 V179T 1 G190A 1

Relation Between Total Score and Virological Response

Etravirine (TMC 125) and Rilpivirine (TMC 278)

Structures of NNRTIs Nevirapine Efavirenz Etravirine TMC125: Molecular flexibility

Structures of NNRTIs TMC125 Etravirine Etravirine Rilpivirine

Single Tablet Regimen Eviplera (Complera) One pill taken once daily containing: Tenofovir 300 mg Emtricitabine (FTC) 200 mg Rilpivirine 25 mg

ECHO and THRIVE: Double-blind, double-dummy studies in treatment-naïve patients 48 weeks primary analysis 96 weeks final analysis ECHO (TMC278-C209) TMC278 25mg qd + TDF/FTC + EFV pbo qd (N=346) N=690 patients 1:1 EFV 600mg qd + TDF/FTC + TMC278 pbo qd (N=344) THRIVE (TMC278-C215) N=678 patients 1:1 TMC278 25mg qd + 2 N(t)RTIs* + EFV pbo qd (N=340) EFV 600mg qd + 2 N(t)RTIs* + TMC278 pbo qd (N=338) *Investigator s choice: TDF/FTC (60%); AZT/3TC (30%); ABC/3TC (10%) Cohen C, et al. HIV10 2010. Abstract O432

48 Week Virologic Outcome of Randomized Treatment Rilpivirine % N=686 Efavirenz % N=682 HIV-1 RNA < 50 83 80 Virologic failure 13 9 Discontinued study due to adverse event or death Discontinued study for other reasons 2 7 2 3 Missing data 1 <1 Pooled Data from the TMC278-C209 and TMC278-C215 Trials Source: FDA Label May 2011

Selected Treatment-Emergent Adverse Drug Reactions of at least Moderate Intensity* (Grades 2-4) Occurring in at Least 2% of Antiretroviral Treatment- Naïve HIV-1 Infected Adult Subjects (Week 48) Rilpivirine % N=686 Efavirenz % N=682 Nausea 1 3 Abdominal pain 1 2 Vomiting 1 2 Fatigue 1 2 Rash 3 11 Nervous System Headache 3 3 Dizziness 1 7 Psychiatric Disorders Depressive disorders 4 3 Insomnia 3 3 Abnormal dreams 1 4 Pooled Data from the TMC278-C209 and TMC278-C215 Trials Source: FDA Label May 2011

Incidence of Depressive Disorders Including:depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation Rilpivirine % N=686 Efavirenz % N=682 Depressive disorders (All severities) Depressive disorders (Grade 3 and 4) Study discontinuation due to depressive disorders 8 6 1 1 1 1 Suicide attempt 2 0 Suicide ideation 1 3 Pooled Data from the TMC278-C209 and TMC278-C215 Trials Source: FDA Label May 2011

Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset VL <50 c/ml by Baseline Viral Load (Snapshot) VL <50 c/ml (%) 100 90 80 70 60 50 40 30 20 10 0 77 RPV 83 77 80 EFV 74 Overall 100K >100K to 500K 73 75 60 >500K Baseline HIV-1 RNA, copies/ml

Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset VL <50 c/ml by Baseline Viral Load (Snapshot) VL <50 c/ml (%) 100 90 80 70 60 50 40 30 20 10 0 77 80 EFV Overall 100K >100K to 500K 73 75 >500K Baseline HIV-1 RNA, copies/ml

Pooled ECHO and THRIVE: Wk 96 FTC/TDF Dataset VL <50 c/ml by Baseline Viral Load (Snapshot) VL <50 c/ml (%) 100 90 80 70 60 50 40 30 20 10 0 77 83 RPV 74 Overall 100K >100K to 500K 60 >500K Baseline HIV-1 RNA, copies/ml

Resistance Among Virological Failures Resistance (Geno + Phen) to study drug Resistance to a background regimen drug Rilpivirine % N=92 Efavirenz % N=60 41 (RPV) 25 (EFV) 48 15 Pooled Data from the TMC278-C209 and TMC278-C215 Trials Source: FDA Label May 2011

FDA Label Update December 2012 The following points should be considered when initiating therapy with Rilpivirine (EDURANT): More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/ml at the start of therapy experienced virologic failure (HIV-1 RNA 50 copies/ml) compared to EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/ml Regardless of HIV-1 RNA at the start of therapy, more rilpivirine treated subjects with CD4+ cell count less than 200 cells/mm 3 experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm 3 The observed virologic failure rate in rilpivirine treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz More subjects treated with rilpivirine developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz FDA Packet Insert, December 2012

Cross Resistance Among NNRTI Stanford HIV Drug Resistance Database, Robert Shafer PI, January 2012

Protease Inhibitors Protease inhibitors RNA RT RNA DNA RT DNA DNA RNA RNA Provirus Proteins

Protease Inhibitors Atazanvir (ATV ATV/r) Darunavir (DRV DRV/r) Lopinavir (LPV LPV/r) fosamprenavir (fapv fapv/r) Indinavir (IDV IDV/r) Saquinavir (SQV SQV/r) Nelfinavir (NFV) Ritonavir (RTV)

Protease Inhibitors Atazanvir (ATV ATV/r) Darunavir (DRV DRV/r) Lopinavir (LPV LPV/r) famp/r No unique benefit higher risk of DRV MU IDV/r No unique benefit higher toxicity SQV/r No unique benefit NFV No unique benefit low genetic barrier RTV No unique benefit high toxicity at 600 x 2 boosting only

Protease Inhibitors Atazanvir (ATV ATV/r) Darunavir (DRV DRV/r) Lopinavir (LPV LPV/r)

Protease Inhibitors Genetic Barrier to Resistance The key feature of boosted protease inhibitors is their high genetic barrier to resistance This is a function of both virology and pharmacology

Genetic Barrier to Resistance: Virology and Pharmacology

Drug level Minimal Plasma level of drug (Cmin) Drug level to inhibit WT virus

Estimating the Barrier to Resistance Minimal Plasma level of drug (Cmin) Drug level to inhibit WT virus

Estimating the Barrier to Resistance Minimal Plasma level of drug (Cmin) Is this the clinically relevant Genetic Barrier to Resistance? Drug level to inhibit WT virus

Correcting for Protein Binding of Drug in Plasma Minimal Plasma level of drug (Cmin) Drug level to inhibit WT virus

Estimating the Barrier to Resistance Minimal Plasma level of drug (Cmin) Drug level to inhibit WT virus corrected for protein binding Drug level to inhibit WT virus

How Much Resistance from a Single Mutation to the Drug Minimal Plasma level of drug (Cmin) Drug level to inhibit most potent single mutation to the drug Drug level to inhibit WT virus corrected for protein binding Drug level to inhibit WT virus

PI/r Summary Resistance: High genetic barrier to resistance Partial cross-resistance between drugs Good activity Retains relatively good activity when partial resistance present Toxicity: Substantial toxicity (somewhat less with ATV/r 300/100) PK: Fair, once daily dosing possible for most drugs but just barely

Integrase Inhibitors RNA RT RNA DNA RT RNA RNA Proteins DNA DNA Provirus Integrase inhibitors

Integrase Inhibitor

Integrase Inhibitors Raltegravir (RAL) Elvitegravir (EVG) Dulotegravir (DTG) - Investigational

Integrase Inhibitor in Active Site RCSB Protein Data Base

Key Raltegravir Mutations Stanford HIV Data Base

Raltegravir

RAL Resistance: Three Pathways N155H Q148K/H/R Y143C L74M L74M E92Q E92Q E92Q T97A T97A T97A V151I V151I E138A G163R G163R E138K S230R G163K S2 30R G140A G140S G163R Witmer et al, ICAAC 2008

Genotype Phenotype Correlations of RAL Mutations 600 Q148 Pathway Fold-Change IC 50 500 400 300 200 100 0 Q148H Q148H/G140S Q148K Q148K/E138A Q148K/G140A Q148K/E138A/G140A Q148R Q148R/G140S

Elvitegravir

EVG: Correlation of EVG and RAL Susceptibility Among Virological Failure Isolates RAL fold-change (relative to NL4-3) 1000 100 10 1 0.1 R 2 = 0.66 G140S/C + Q148H/R/K G140S + Q148K mixture E138K + S147G + Q148R Other IN mutation patterns No change 1 10 100 1000 EVG fold-change (relative to NL4-3) McColl DJ et al. Antiviral Therapy 2007;12:Abstr. 9.

Quad Pill - Stribild Elvitegravir 150 mg Cobicistat 150 mg Emtricitabine 200 mg Tenofovir disoproxil fumarate 300 mg

Study Design n=350 Treatment- naive Any CD4 count Quad QD EFV/FTC/TDF QHS Placebo n=350 EFV/FTC/TDF QHS Quad Placebo QD Week 48 Week 192

Week 48 and 96 HIV-1 RNA < 50 Percentage of subjects (%) 100 80 60 40 20 88% 84% 84% 82% 7% 7% 9% 6% 8% 9% 11% 5% 0 W48 W96 W48 W96 W48 W96 Virologic Success Virologic Failure No data at W48 (or 96) QUAD (STBD) EFV/FTC/TDF (ATR)

Common Adverse Events Quad (n=348) Treatment Emergent Adverse Events in 10% of subjects (%) EFV/FTC/TDF (n=352) Diarrhea 23% 19% Nausea * 21% 14% Abnormal Dreams ^ 15% 27% Upper Respiratory Infection 14% 11% Headache 14% 9% Fatigue 12% 13% Insomnia * 9% 14% Depression 9% 11% Dizziness ^ 7% 24% Rash # 6% 12% * p < 0.05 ^ p < 0.001 # p=0.009

Median Change from Baseline in Serum Creatinine Change from BL in Serum Creatinine (mg/dl) (IQR) 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0.00-0.05-0.10 BL 2 4 8 12 16 24 32 40 48 Week

Integrase & NNRTI Resistance Through Week 48 Quad (n=348) EFV/FTC/TDF (n=352) Subjects Analyzed for Resistance*, n (%) 14 (4) 17 (5) Subjects with Resistance to ARV Regimen, n (%) 8 (2) 8 (2) Any Primary Integrase-R, n 7 Any Primary NNRTI-R n 8 Any Primary NRTI-R, n 8 2 *Subjects who experienced either suboptimal virologic response or rebound or had HIV-1 RNA 400 c/ml at their last visit.

Quad Compared to ATV/r + Truvada in Treatment Naive HIV-1 Infected Subjects (n=350) Quad QD Treatment naive ATV/r+FTC/TDF Placebo QD (n=350) ATV/r + FTC/TDF QD Quad Placebo QD Week 48 Week 192 E DeJesus et al 19 th CROI, Seattle, March 7, 2012. Poster # 627

Quad Compared to ATV/r + Truvada Week 48 HIV RNA < 50

Integrase, PI, NRTI Resistance Through Week 48 Quad (n=353) ATV/r + FTC/TDF (n=355) Subjects Analyzed for Resistance a, n (%) 12 (3) 8 (2) Subjects with Resistance to ARV Regimen, n (%) 5 (1) 0 Any Primary Integrase-R, n 4 - Any Primary PI-R, n - 0 Any Primary NRTI-R, n 4 0 Subjects who experienced either suboptimal virologic response or rebound or had HIV-1 RNA 400 c/ml at their last visit.

Dolutegravir

Dolutegravir: Rapid and Durable Antiviral Activity Week 96 Efficacy Analysis (<50 c/ml) Percent Subjects with HIV-1 RNA <50 c/ml (TLOVR) 88% 79% 78% 72% Week 95% confidence intervals are derived using the normal approximation. Stellbrink et al,19 th CROI, Seattle, March, 2012

Dolutegravir Treatment Response and Safety by Key Subgroups in Treatment Naive HIV Infected Individuals Subgroup analysis of DTG studies in drug naïve patients SPRING 2: DTG versus RAL SINGLE: DTG versus EFV Brinson C et al. CROI 2013 Atlanta. Abstract 554

Proportion With Plasma HIV RNA <50 at Week 48 FDA Snapshot Brinson C et al. CROI 2013 Atlanta. Abstract 554

Adverse Events Leading to Withdrawal Brinson C et al. CROI 2013 Atlanta. Abstract 554

Antiviral Activity of Dolutegravir in Subjects With Failure on an Integrase Inhibitor-Based Regimen: Week 24 Phase 3 Results From VIKING-3 HIV-1 RNA 500 copies/ml *Resistance to RAL and/or EVG *Resistance to 2 ART classes other than INIs Functional monotherapy phase DTG 50 mg BID and continue failing regimen Optimised phase DTG 50 mg BID + optimised background regimen with OSS 1 Screening period up to a maximum of 42 days Screening visit ~Day -35 Day 1 Day 8 Week 24 analysis *Screening or documented historical evidence. Week 48 analysis Nichols, G. et al. HIV11, Glasgow, UK; 11-15 November 2012 ; Oral # O232.

Day 8 and Week 24 Efficacy Endpoints 100 Day 8 change from BL: -1.43 log 10 copies/ml, P<0.001 95% CI, -1.52 to -1.34 (ITT-E, N=183) Week 24 by Snapshot (MSDF): 72/114 (63%) <50 copies/ml 37/114 (32%) were virologic non-responders - 6/114 (5%) changed OBR Only 5/114 (4%) were nonresponders for discontinuation due to AEs Percentage of subjects with HIV-1 RNA <50 copies/ml 90 80 70 60 50 40 30 20 10 0 Overall, 63% were fully suppressed at Week 24 by Snapshot algorithm BL D8 W4 W8 W12 W16 W24 Time Week 24 population (N=114) was those subjects who had opportunity to reach Week 24 at time of data cut-off Nichols, G. et al. HIV11, Glasgow, UK; 11-15 November 2012 ; Oral # O232.

Dolutegravir (DTG) Versus Raltegravir (RAL) in ART- Experienced, Integrase-Naive Subjects: 24-Week Interim Results From SAILING (ING111762) Pozniak A et al. CROI 2013 Atlanta. Abstract 179LB

Baseline Characteristics Pozniak A et al. CROI 2013 Atlanta. Abstract 179LB

Week 24 Results Pozniak A et al. CROI 2013 Atlanta. Abstract 179LB

Integrase Inhibitor Summary Resistance: Very potent and rapid activity RAL and EVG broad cross-resistance Apparent less cross resistance with DTG Toxicity: Very few toxicities (currently appears to be very well tolerated and safe) PK: RAL BID EVG QD with boosting DTG QD without boosting (BID may increase genetic barrier further)

Summary Many excellent antiretroviral drugs are now available for HIV infected patients Both veteran and newer classes offer advantages in certain combinations and clinical situations Virological and pharmacological characteristics such as the genetic barrier to resistance and drug half life differ not only between classes, but also among agents of the same class These factors need to be considered when making therapeutic decisions