HIV Treatment Update

Transcription

1 HIV Treatment Update Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, NM Johns Hopkins University School of Medicine University of New Mexico School of Medicine Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Merck & Co. Theratechnologies ViiV Healthcare/GSK Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare/GSK 1

2 DHHS Guidelines, July 216: What to Start Recommended regimens PI based DRV/r + (TDF/FTC or TAF/FTC) INSTI based DTG + (TDF/FTC or TAF/FTC) DTG/ABC/3TC EVG/c/TDF/FTC or EVG/c/TAF/FTC RAL + (TDF/FTC or TAF/FTC) Alternative regimens NNRTI based EFV/TDF/FTC or EFV + TAF/FTC RPV/TDF/FTC or RPV/TAF/FTC (VL <1,; CD4 >2) PI based (ATV/c or ATV/r) + (TDF/FTC or TAF/FTC) (DRV/c or DRV/r) + ABC/3TC DRV/c + (TDF/FTC or TAF/FTC) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, July 216. IAS USA Guidelines, July 216: What to Start Recommended Regimens DTG/ABC/3TC DTG + FTC/TAF EVG/c/FTC/TAF RAL + FTC/TAF Regimens When INSTIs are Not an Option DRV/c or DRV/r + (FTC/TAF, FTC/TDF or ABC/3TC) EFV/FTC/TDF RPV/FTC/(TAF or TDF) Günthard HF, et al. JAMA 216;316:

3 TAF vs. TDF: Mechanism of Action GI TRACT PLASMA RENAL TUBULAR CELL LYMPHOCYTE TDF (tenofovir disoproxil fumarate) 3 mg TFV TFV HIV TAF (tenofovir alafenamid e) 25 mg 91% lower plasma TFV RENAL TUBULAR CELL 1. Lee W et al. Antimicr Agents Chemo 25;49: ; 2. Birkus G, et al. Antimicr Agents Chemo 27;51:543-5; 3. Babusis D, et al. Mol Pharm 213;1:459-66; 4. Ruane P, et al. JAIDS 213;63:449-5; 5. Sax P, et al. JAIDS 214;67:52-8; 6. Sax P, et al. Lancet 215;385: GS 14/111: Initial ART with E/C/F/TAF v. E/C/F/TDF Parallel, randomized, double-blind, active-controlled phase III studies 1 o endpoint: VL < 5 at Wk 48 (FDA Snapshot) Stratified by VL, CD4 count, geographic region Wk 48 Primary endpoint Wk 144 ART-naïve pts with VL 1, egfr 5 ml/min (N = 1733) EVG/COBI/FTC/TAF (n = 866) EVG/COBI/FTC/TDF (n = 867) Arribas JR, et al. CROI 217. Abstract 453. Sax PE, et al. Lancet. 215;385:

4 Initial ART with E/C/F/TAF v. E/C/F/TDF: 144 Week Efficacy Treatment Difference Wk 48: 2.% (95% CI: -.7% to 4.7%) Wk 144: 4.2% (95% CI:.6% to 7.8%; P =.2) E/C/F/TAF (N=886) E/C/F/TDF (N=867) Virologic success Virologic Failure No data Arribas JR, et al. CROI 217. Abstract 453. Sax PE, et al. Lancet. 215;385: Efficacy similar across subgroups, trending toward or significantly better with TAF in each group By baseline VL, baseline CD4, adherence, age, sex, race, region Virologic failure with resistance by Wk 144: 1.4% in each arm Initial ART With E/C/F/TAF vs E/C/F/TDF: 144 Week Safety Outcomes More discontinuation for AEs with TDF vs TAF 3.3% vs 1.3% (P =.1) Greater spine and hip BMD loss with TDF vs TAF 6 D/C s for bone AEs in TDF arm vs in TAF arm TC, LDL, and HDL increases greater with TAF vs TDF Rates of lipid-modifying therapy initiation similar: 5.5% vs 5.8% Med. egfr increase lower with TAF vs TDF regimen: 1.6 vs 7.7 ml/min (P <.1) Renal Events Leading to Discontinuation, n Proximal renal tubulopathy Cr elevation or egfr decrease TAF (n = 866) TDF (n = 867) 4 3 Renal failure 2 Nephropathy 1 Proteinuria 1 Bladder spasm 1 Total 12 Arribas JR, et al. CROI 217. Abstract

5 ARIA: DTG/ABC/3TC vs. ATV/r + FTC/TDF in ART-Naive Women at Wk 48 VL < 5 (%) n/n = DTG/ABC/3TC / 176/ Virologic Outcome 148/ 134/ Overall 1K > 1K 35 > 35 VL 55/ 69 42/ 66 ATV/r + FTC/TDF / 89/ CD4 Count 92/ 87/ Overall Treatment Difference (95% CI) Favors ATV/r + FTC/TDF Favors DTG/ABC/3TC P =.5 2 Outcome, % (n) DTG/ABC/3TC ATV/r + FTC/TDF (n = 248) (n = 247) Virologic nonresponse 6 (16) 14 (35) No virologic data 12 (29) 15 (36) Orrell C, et al. AIDS 216. Abstract THAB25LB. Johnson M, et al. HIV Glasgow 216. Abstract P35. Hagins D, et al. IDWeek 216. Abstract 949. WAVES: Switch to E/C/F/TAF in Women at Wk 48 Open-label extension study VL < 5 (%) Virologic Outcome Switch to EVG/c/FTC/TAF (n = 159) Continue ATV/r+FTC/TAF (n = 53) Success Failure No Data n= Treatment Difference (95% CI) Favors ATV/r + FTC/TAF Favors E/c/F/TAF Hodder S, et al. CROI 217. Abstract

6 Integrase resistance in the U.S. Transmitted INSTI resistance remains rare; rates of on-treatment INSTI resistance remains low [1-3] CDC National HIV Surveillance System [1] : Prevalence of INSTI resistance through 214: 65/14,468 (.4%) Pre-ART prevalence of INSTI resistance (ie, transmitted): 2/4631 (.4%) UNC CFAR HIV Clinical Cohort [2] : 215 INSTI resistance prevalence in 685 pts who began ART in 27 or later: 1% Modeling: assuming.1% rate of transmitted INSTI resistance and $25 cost per test: pre-art INSTI resistance testing correlated with worse outcomes, higher costs vs no test [3] 1. Hernandez AL, et al. CROI 217. Abstract Davy T, et al. CROI 217. Abstract Koullias Y, et al. CROI 217. Abstract 493. Emergence of INSTI Resistance in Acute Infection Treated With DTG + FTC/TDF 45-yo man with PCP and ARS Started DTG + FTC/TDF and discharged; readmitted to ICU several days later for hypoxia VL increased after readmission despite adherence (including DOT in hospital); no divalent cation use DRV/r added, VL decreased Pneumonia improved; pt discharged Rapid INSTI emergence by deep seq: eg, Q148K population increased from.15% at Timepoint 1 to 2.9% at Timepoint 3 VL (c/ml) Initiated DTG/FTC/TDF; GT (clinical assay): RT: V118I, F214L; IN: Not Tested Added DRV/RTV; GT (clinical assay): RT: M184V, V118I, F214L; IN: G163E Time Points of IN Deep sequencing Days CD4+ Count (cells/mm 3 ) Fulcher JA, et al. CROI 217. Abstract 5LB. 6

7 D:A:D: Exposure to ATV/r or DRV/r and Risk of CVD Prospective analysis of pts followed from 1/1/9 (BL) to earliest CVD, last visit + 6 mos, or 2/1/16 (N = 35,711) 1157 (3.2%) developed CVD (MI, CVA, sudden cardiac death, invasive CV procedure) Cumulative expos. to DRV/r, but not ATV/r, assoc. with increased CVD risk in multivariate analysis: 59% risk increase per 5-yrs DRV/r Not mediated by dyslipidemia, in contrast with 1 st -generation PIs CVD Risk per 5 Yrs of ARV Exposure, IRR (95% CI) Model ATV/r DRV/r Univariate Multivariate Baseline adjusted* Time-updated adjusted* 1.25 ( ) 1.3 ( ) 1.1 ( ) *Adjusted for: BMI, CKD, DM, CD4, dyslipidemia ( ) 1.59 ( ) 1.53 ( ) Limitations: potential for unmeasured confounding; observational study; unable to distinguish between DRV/r8/1 mg QD vs DRV/r 6/1 mg BID Ryom L, et al. CROI 217. Abstract 128LB. Initial Therapy: My choices for specific clinical scenarios Scenario Desires single-tablet regimen (STR) STR doesn t matter HBV Coinfection Starting without resistance test results Desire for pregnancy Questionable adherence Tuberculosis Drug interactions (including HCV) Regimens DTG/ABC/3TC EVG/c/FTC/TAF DTG + FTC/TAF FTC/TAF-based regimen (DRV/c or DTG) + FTC/TAF RAL + (FTC/TDF or ABC/3TC) DRV/r + (FTC/TDF or ABC/3TC) DTG/ABC/3TC DRV/c + FTC/TAF EFV/FTC/TDF RAL 8 mg bid + (FTC/TDF or ABC/3TC) DTG or RAL-based regimen 7

8 When to Start?: Guidelines Symptoms CD4 <2 CD CD CD4 >5 US DHHS YES YES YES YES YES IAS-USA YES YES YES YES YES EACS YES YES YES YES YES BHIVA (UK) YES YES YES YES YES WHO YES YES YES YES YES T.F. 28-year-old gay man presents with 3 days of fever, night sweats, lymphadenopathy, and sore throat. A rapid 4 th generation HIV test is positive Tested negative 6 months ago. Has been having condomless sex with multiple partners. He asked his primary care provider about PrEP and was told he would have to see a specialist. Otherwise in good health. Has well controlled depression on citalopram. He has been vaccinated against hepatitis B. Sees a nurse and case manager the day after diagnosis, and baseline lab tests are drawn. Has appointment with HIV provider in 1 days. Wants to start ART as soon as possible 8

9 T.F. When would you start ART? 1. After he keeps several clinic appointments (~3 months) 2. After baseline genotype results are available (~2-3 weeks) 3. At the HIV provider visit (1 days) 4. If creatinine is normal and HBsAg is negative (1-2 days) 5. Today RAPID Start: Time to VL suppression by ART initiation strategy: SFGH Proportion <2 c/ml RAPID N = 39 Universal ART CD4-guided ART RAPID vs. universal ART p<.1 Pilcher CD, et al. J Acquir Immune Defic Syndr 216 9

10 Rapid Start: Potential regimens Regimens to consider DTG + FTC/TAF EVG/c/FTC/TAF DRV/c + FTC/TAF Drugs to avoid ABC (need HLA B*571) TDF (need egfr) RPV (need VL, CD4) EFV, NVP (need genotype) Switching Therapy 1

11 Summary of TAF Switch Studies in Virologically Suppressed Patients Trials: GS-19: TDF-containing regimens to EVG/COBI/FTC/TAF GS -112: Switch to EVG/COBI/FTC/TAF in patients with impaired renal function GS-119: ART + DRV/r to EVG/COBI/FTC/TAF + DRV in ART-experienced patients GS-189: FTC/TDF to FTC/TAF GS-116: EFV/FTC/TDF to RPV/FTC/TAF GS-1216: RPV/FTC/TDF to RPV/FTC/TAF Results:. Noninferiority, with superiority in GS-19 (switch from EFV/FTC/TDF or ATV/r + FTC/TDF) and superiority in GS-119 Increase in bone density Stability of egfr (increase in GS-189 and GS-112) with no tubular toxicity and decrease in overall and tubular proteinuria GS 189: Switch from F/TDF to F/TAF Weeks 48 and 96 Efficacy Virologic Outcome Treatment Difference (95% CI) FTC/TAF (n=333) FTC/TDF (n=33) FTC/TDF FTC/TAF Patients, % Wk Week Wk Success (< 5 copies/ml) Failure No Virologic Data FTC/TAF noninferior to FTC/TDF at Weeks 48 and 96 Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 11

12 GS 189: Switch from F/TDF to F/TAF Change in Renal Biomarkers at Weeks 48 and 96 FTC/TAF FTC/TDF Median Change, ml/min egfr 1 4 Median % Change Urine Protein:Cr Urine Albumin:Cr 3 27 Urine RBP:Cr Urine β2m:cr All differences between treatments statistically significant (p <.1) Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 GS 189: Switch from F/TDF to F/TAF: Bone density changes through Week 96 Spine Hip Mean % Change (95% CI) p < p < n Week Week FTC/TAF FTC/TDF FTC/TAF FTC/TDF p value FTC/TAF FTC/TDF p value 3% increase 4% 18% <.1 29% 11% <.1 3% decrease 8% 19% <.1 6% 15% <.1 Raffi F, et al. HIV Glasgow, October 216, Glasgow, UK, Presentation O125 12

13 TDF to TAF switch Advantages: Increased egfr Decreased proteinuria Improved bone density Smaller pill size Disadvantages: Loss of TDF lipid effect TAF will be more expensive than generic TDF IAS-USA recommendations: If there is no increase in the price of TAF vs. that of TDF, switching from TDF to TAF is reasonable even if patients are not experiencing TDF-related toxic effects. Günthard HF, et al. JAMA 216;316: Alternative Strategies Using Approved Drugs 13

14 SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV Pts (%) HIV-1 RNA < 5 c/ml Treatment difference: -.2% (95% CI: -3.% to 2.5%) < 1 1 Virologic Nonresponse Llibre JM, et al. CROI 217. Abstract 44LB. DTG + RPV (n=513) Baseline ART (n=511) 5 4 No Data Open-label, multicenter phase III trials of pts with virologic suppression (N=124) randomized to continue baseline ART vs switch to DTG + RPV 1 pt with confirmed criteria for virologic withdrawal at Wk 36 in DTG + RPV arm had K11K/E Documented nonadherence at VF Resuppressed with continued DTG + RPV No INSTI resistance SWORD 1 & 2: Switch From Suppressive ART to DTG + RPV: Safety Outcomes Mean (µg/l) DTG + RPV Baseline ART 1 Baseline Baseline Wk 48 Wk 48 8 P < P < Bone-specific alkaline phosphatase P <.1 Osteocalcin Procollagen 1 N-terminal propeptide Bone Turnover Markers Llibre JM, et al. CROI 217. Abstract 44LB AE rates generally similar between arms through Wk 52 Numerically higher rate of drug-related grade 1/2 AEs with switch: 17% vs 2% Numerically higher rate of withdrawal for AEs with switch: 4% vs < 1% No notable change in lipids through Wk 48 in either treatment arm 14

15 PADDLE: Dolutegravir + Lamivudine for Treatment-Naive Pts HIV-1 RNA (copies/ml) Pt # Screen BL Day 2 Day 4 Day 7 Day 1 Wk 2 Wk 3 Wk 4 Wk 6 Wk 8 Wk 12 Wk 24 Wk 36 Wk , < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < , < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < , ,569 37, < 5 < 5 < 5 < 5 < 5 < 5 < , ,37 11, < 5 < 5 < 5 < 5 < 5 < 5 < ,362 2, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,24 14, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,64 18, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,71 24, Not done < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,77 1,832 Not done < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 SAE 1 1, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,89 273,676 16,974 68, < 5 < 5 < 5 < 5 < ,58 64, < 5 < 5 < 5 < 5 < 5 < ,93 33,829 37,35 26, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,348 15, < < 5 < 5 < 5 < 5 < 5 < ,185 23,5 15, < 5 < 5 < 5 Not done < 5 < 5 < 5 < 5 < , < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,1 25,828 11, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,771 73,69 31, < 5 < 5 < 5 < 5 < 5 < 5 < 5 < ,83 16,32 35, < 5 < 5 < 5 < 5 < 5 Virologic failure < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 < 5 Cahn P, et al. AIDS 216. Abstract FRAB14LB. ANRS 167 LAMIDOL: Switch to DTG + 3TC in Suppressed Pts Noncomparative, open-label, single-arm multicenter trial 1 o endpoint: therapeutic success at Wk 56 (ie, after 48 wks of dual therapy) Therapeutic failure: VL > 5 interruption, lost to f/u, death VL 5 x 2 yrs on 1st-line ART; 2 ART modifications, except within 6 mos of study start; CD4 > 2 (N = 11) Phase I DTG + 2 NRTI Wk 8* Wk 56 Phase II DTG + 3TC (n = 14) *Pts with VL 5 proceeded to phase II. In phase I, third agent in regimen replaced with DTG; baseline NRTI backbone maintained. Joly V, et al. CROI 217. Abstract

16 ANRS 167 LAMIDOL: Switch to DTG + 3TC in Suppressed Pts 97% (11/14) remained suppressed through 4 wks of dual therapy (study Wk 48) [1] No INSTI resistance in 3 pts with virologic failure 7 with SAEs, only 2 related to dual therapy Switch to DTG-based dual therapy vs continued triple ART currently under evaluation in several phase III trials [2,3] 1. Joly V, et al. CROI 217. Abstract ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT Therapeutic Success, n/n* (%) DTG + 3TC Wk (entry; on BL triple therapy) 11/11 (1) Wk 8 (end of phase I, start of phase II) 14/14 (1) Wk 12 14/14 (1) Wk 16 13/14 (99) Wk 24 13/14 (99) Wk 32 13/14 (99) Wk 4 12/14 (98) Wk 48 11/14 (97) *Pts enrolled in phase I, N = 11; pts enrolled in phase II, N = 14. DOMOMO: Switch to DTG Monotherapy in Virologically Suppressed Pts Randomized comparison: switch to DTG monotherapy vs continued baseline ART for 24 wks in suppressed pts without previous VF [2] At Wk 24, DTG monotherapy noninferior to continued baseline ART (VL <2) After 24 wks, all pts allowed to switch to monotherapy Study stopped early because of high VF rate after 48 wks of monotherapy VF in 8/77 pts with DTG monotherapy vs 3/152 pts on combination ART in concurrent control group (P =.3) Among 6 VF cases with resistance data in DTG monotherapy group, 3 developed INSTI resistance Wijting I, et al. CROI 217. Abstract 451LB. 16

17 Emergent INSTI Resistance After Switch to DTG Monotherapy International, multicenter retrospective study Evaluated virologically suppressed pts switched to DTG monotherapy Pts with history of VF on INSTI and INSTI resistance excluded 11 of 122 pts (9%) switched to DTG monotherapy experienced VF 9 of 11 had genotypic INSTI resistance at VF Blanco JL, et al. CROI 217. Abstract 42. INSTI resistance pathways varied INSTI Resistance at VF 92Q/155H (n = 1) 97A/155H (n = 1) 155H/148R (n = 1) 118R (n = 2) 148K (n = 1) 148H (n = 2) 148R (n = 1) Investigational Drugs 17

18 Doravirine vs. DRV/r at Wk 48 FDA Snapshot Pts (%) HIV-1 RNA < 5 c/ml DOR + 2 NRTIs (n = 383) DRV/r + 2 NRTIs (n = 383) Treatment difference: 3.9% (95% CI: -1.6% to 9.4%) Virologic Nonresponse Wk No Data Efficacy similar in both arms regardless of baseline VL or CD4 count No resistance detected in pts with PDVF through Wk 48 in either arm n = 1 pt with noncompliance discontinued at Wk 24, developed DOR and FTC resistance Molina JM, et al. CROI 217. Abstract 45LB. Doravirine vs DRV/r in Combination With FTC/TDF or ABC/3TC: Safety AE, % DOR (n = 383) DRV/r (n = 383) 1 AE 8 78 Treatment-related AE Serious AE 5 6 Discontinuation for AE 2 3 AEs of clinical interest Rash* Neuropsychiatric Fasting Lipid Δ From BL to Wk 48, mg/dl DOR (n = 383) DRV/r (n = 383) LDL-c* Non-HDL-c* Cholesterol Triglyceride HDL-c *P <.1 for DOR vs DRV + RTV. *Discontinued due to rash: n = 2 in DOR arm; n = 1 in DRV/r arm. No discontinuation for neuropsychiatric conditions. Molina JM, et al. CROI 217. Abstract 45LB. 18

19 Bictegravir + FTC/TAF vs DTG + FTC/TAF in Treatment-Naive Pts Bictegravir: novel QD INSTI, active against most INSTI mutations, low DDI potential, half-life ~ 18 hrs, no food requirement with dosing, primarily metabolized by CYP3A4 and UGT1A1 Randomized, double-blind, active-controlled phase II trial Primary endpoint: VL < 5 at Wk 24 Wk 24 Wk 48 ART-naive pts with VL 1; CD4 2; HBV and HCV negative (N = 98) BIC + FTC/TAF QD + Placebo for DTG QD (n = 65) DTG + FTC/TAF QD + Placebo for BIC QD (n = 33) Openlabel extension Sax PE, et al. CROI 217. Abstract 41. Sax PE, et al. Lancet HIV. 217;[Epub ahead of print]. Zhang H, et al. CROI 217. Abstract 4. Bictegravir + FTC/TAF vs DTG + FTC/TAF: Wk 24 and Wk 48 Efficacy (FDA Snapshot) No drug resistance detected in either arm through Wk BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33) Pts (%) 6 4 Treatment difference: 2.9% (95% CI: -8.5% to 14.2%) 6 4 Treatment difference: 6.4% (95% CI: -6% to 18.8%) 2 Virologic Success 3 6 Virologic Failure Wk 24 No Data 2 Virologic Success 2 6 Virologic Failure Wk No Data Sax PE, et al. CROI 217. Abstract

20 Bictegravir + FTC/TAF vs DTG + FTC/TAF: AEs and Lab Abnormalities Any Grade AE Occurring in 5% in Either Arm, % BIC + FTC/TAF (n = 65) DTG + FTC/TAF (n = 33) Diarrhea Nausea 8 12 Headache 8 3 URTI 8 Fatigue 6 6 Arthralgia 6 6 Chlamydial infection 6 3 Back pain 6 Furuncle 5 6 Flatulence 2 6 Gastroenteritis 2 6 Costochondritis 6 Hemorrhoids 6 Sax Pruritus PE, et al. CROI 217. Abstract 41. Reproduced with permission. 6 Grade 2-4 Lab Abnormality 5% in Either Arm, % BIC + FTC/TAF (n = 64*) DTG + FTC/TAF (n = 32*) Creatine kinase 13 9 AST 9 3 Hyperglycemia 8 13 ALT 6 LDL 6 9 Amylase 5 6 Hematuria 3 6 Glycosuria 2 6 Difficult to drawn conclusions on safety from small study, but 4 fully enrolled phase III trials in progress now evaluating efficacy, safety, tolerability of coformulated BIC/FTC/TAF *Pts with 1 post-bl laboratory assessment, excluding those not specified for all pts. Sax PE, et al. CROI 217. Abstract 41. LATTE-2: IM cabotegravir + rilpivirine Week 48 Results: VL <5 Snapshot (ITT-ME) Induction period Maintenance period Proportion of patients with virological suppression, % Snapshot success D1 W32 Q4W 99% 94% Q8W 95% 95% Oral 98% 91% BL W-16 W-12 W-8 W-4 D1 W4 W8 W12 W16 W2 W24 W28 W32 W36 W4 W44 W48 Study visit Oral CAB induction (ME population) Oral CAB (n=56) Q4W IM (n=115) Q8W IM (n=115) Margolis et al. AIDS 216; Durban, South Africa. Abstract THAB26LB. 2

21 LATTE-2 VL <5 at Week 48 ITT-ME (Snapshot) Virologic outcomes Treatment differences (95% CI) Oral Q8W IM IM Q4W IM Both Q8W and Q4W comparable to Oral CAB at Week 48 a 2 subjects with resistance in 8 wk arm: 1 with INSTI mutations, 1 with NNRTI mutations Margolis et al. AIDS 216; Durban, South Africa. Abstract THAB26LB. MK-8591: Long-acting NRTI Active phosphorylated metabolite has prolonged intracellular half-life in PMBCs: hrs Exploratory study of single 1 mg oral dose in HIV infected volunteers Potential for novel dosing or administration strategies Change From Baseline VL (log 1 c/ml) TDF - 3 mg QD TAF - 25 mg QD MK mg QW Time (days) Grobler J, et al. 23rd CROI; Boston, MA; February 22-25, 216. Abst. 98; Friedman E, et al. 23rd CROI; Boston, MA; February 22-25, 216. Abst. 437LB. 21

22 Possible Long Acting Subdermal Implantable Devices for TAF Delivery Silicone scaffold diffusion system 1 Long-acting biodegradable polycaprolactone thinfilm membrane 2 Gunawardana M et al. Antimicrob. Agents Chemother. 215;59: Johnson L, et al. CROI 216. #879. TMB-31: Long-Acting Ibalizumab in Pretreated Pts Infected With Multidrug-Resistant HIV Humanized mab to conformational epitope on CD4 receptor that blocks postattachment HIV entry into CD4 cells without altering normal cell function Single-arm, open-label phase III trial Primary endpoint:.5 log 1 VL decrease at Day 14 VL> 1; on ART 6 mos, on stable ART 8 wks; resistant to 1 ARV from 3 classes, sensitive to 1 ARV for OBR (N = 4) Control Period: Day -7 Ibalizumab 2 mg IV Day 7 (loading dose) Continue Failing ART Days -14 Primary Endpoint: Day 14 Ibalizumab 8 mg IV Day 21, Q2W (maintenance dose) Switch to OBR Day 14 Wk 25 53% with resistance to all drugs from 3 classes; 68% with INSTI resistance Lewis S, et al. CROI 217. Abstract 449LB. 22

23 Efficacy, Safety of Ibalizumab Through 24 Wks 1 o endpoint: 83% with.5 log 1 VL decrease at Day 14 vs 3% at end of control period (P <.1) 6% with 1. log 1 VL decrease Mean decrease by Day 14: 1.1 log Wk 24 Virologic Outcome Ibalizumab + OBR 1. log 1 VL decrease, % log 1 VL decrease, % 48 VL < 5, % 43 VL < 2, % 5 Mean VL decrease from baseline, log 1 9 pts reported 17 serious AEs 1 drug-related serious AE (IRIS) resulted in discontinuation 9 other pts discontinued Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma) Consent withdrawal (n = 3) Lost to follow-up (n = 2) No cases of anti-ibalizumab antibodies Lewis S, et al. CROI 217. Abstract 449LB. Additional Investigational Agents Reported at CROI 217: Preclinical and Phase I Agent MoA or Formulation Pha se Dosing/ Administration Implications GS-CA1 [1] HIV capsid inhibitor Preclinica l Extended release, suitable for SC of solid depot formulation Potent ART with orthoganol resistance profile to existing ART; potential for long-acting formulation due to low aqueous solubility, high stability GS-9131 [2] NRTI Preclinica l Potential for once daily dosing Potent ART active against NRTI RAMs K65R, L74V, M184V alone or in combination; minimal loss of susceptibility with 4 or more TAMs MK-8591 [3] Nucleoside Reverse Transcriptase Translocation Inhibitor (NRTTI) Preclinica l 1 mg QW PO; potential for extended duration Comparable MK-8591 levels in animal rectal, vaginal tissue to TDF levels in tissues of human subjects highlights potential prophylaxis utility GS-PI1 [4] PI Preclinica l Potential for unboosted, once daily dosing Potent ART with high barrier to resistance, including < 2-fold loss in potency against major PI RAMs, and 1- fold to 4-fold longer in vivo half life vs ATV or DRV NANO-EFV, NANO-LPV [5] Oral, lower dose SDN I nefv: 5 mg QD, 21 d nlpv/rtv: 2/1 mg BID, 7 d Enhanced oral bioavailability suggests can reduce EFV, LPV dose by ~ 5% while maintaining PK 1. Tse WC, et al. CROI 217. Abstract White KL, et al. CROI 217. Abstract Grobler J, et al. CROI 217. Abstract Link JO, et al. CROI 217. Abstract Owen A, et al. CROI 217. Abstract

24 Additional Investigational Agents Reported at CROI 217: Phase II Agent TMC278 LA [1] Elsulfavirine [2] UB-421 [3] MoA or Formulation Phase Dosing/ Implications Administration LA injectable II 12 mg IM Q8W Potential as injectable, long-acting PrEP RPV (IM) Prodrug of new NNRTI VM15A Anti-CD4 receptor mab IIb II Combined therapy: 2 mg elsulfavirine + FTC/TDF PO QD 1 mg/kg QW IV or 25 mg/kg Q2W IV Less toxic alternative to EFV for initial ART Possible ART alternative for maintenance therapy in virologically suppressed pts PRO-14[4] Anti-CCR5 mab IIb 35 mg SC/wk Being studied for both monotherapy and combination therapy 1. Bekker L-G, et al. CROI 217. Abstract 421LB. 2. Murphy R, et al. CROI 217. Abstract 452LB. 3. Wang C-Y, et al. CROI 217. Abstract 45LB. 4. Lalezari J, et al. CROI 217. Abstract 437. Conclusions Integrase inhibitor-based regimens are now the standard of care for initial therapy TAF/FTC is the preferred NRTI backbone for all regimens except DTG/ABC/3TC Some regimens allow for immediate ART initiation while awaiting baseline labs results Switching from TDF to TAF increases bone density and egfr and decreases proteinuria Stay tuned for The Great Debate: 3 drugs vs. 2 DTG resistance can happen but is rare except with DTG monotherapy. Don t do it! New drugs keep coming, including long-acting agents 24

25 Thank you! 25