Simplified regimens: Pros and Cons

Transcription

1 Rio de Janeiro, 2018 Simplified regimens: Pros and Cons Pedro Cahn

2 Treatment Strategies: A long way Monotherapy Dual therapy STIs Triple therapy Non daily regimens Simplification Mega HAART Long Acting/Extended Release Regimens

3 PLHIV are aware their treatments have long-term effects 73% of participants (n = 1,111) sometimes worried about the long-term effects of their HIV medication 1 Reduction of long-term AEs and longer treatment intervals were viewed as more important potential medication improvements than reduction of side effects and pill burden 1 Score (100 = average importance) Weight, % Reduces long-term effects of HIV medicine on my body Longer lasting so I can take treatment less often (e.g. monthly injection administered by a doctor/nurse) Fewer side effects Can take less HIV medicine and get the same effect Does not cause a problem with medication I currently take for other illnesses Fewer pills each day No food restrictions or requirements Smaller pill sizes AE, adverse event; PLHIV, people living with HIV. 1. Marcotullio S, et al. EACS 2017, poster PE25/9. Man by Bluetip Design, clock by Three Six Five, dizzy by Gan Khoon Lay, fewer pills by Alex Arseneau, chemical reaction by Maxim Basinski, pills by Daniel DeLorenzo, food by Gregor Cresnar, capsule by Chameleon Design; all from the Noun Project

4 Respondents (%) PLHIV are interested in new antiretroviral approaches, including longer-acting formulations How interested would you be in switching to a new treatment that involves Two small plastic implants in forearm every 6 months Two shots in clinic EOM Single pill QW Survey n = Not at all interested Somewhat interested 4 5 Very interested EOM, every other month; PLHIV, people living with HIV; QW, every week. Osterman J, et al. CROI 2018, poster 503.

5 HAART: Is it about number of drugs or about potency and safety?

6 Reducing drug burden in HAART: Why would you do that? To reduce ARV exposure making treatment safer without sacrificing virologic control To reduce pill burden/improved patient adherence and quality of life To reduce drug-drug interactions To reduce cost Potential for longer-term success Downstream options with spared class in case of first-regimen failure

7 Reducing drug burden in HAART: Potential disavantages Reduced potency? Less forgivness for missing doses? Reduced penetration in sanctuaries? More frequent viral load monitoring? Less durability? Loss of TDF lipid-lowering effect Contraindicated in HBV coinfection (3TC-based DT)

8 Dual Therapy: not always good LPV/r - EFV ATV/r - EFV LPV/r - NVP Good virological response, but increased rate of side effects ATV 300 mg BID + RAL (SPARTAN) MVC QD + DRV/RTV (MODERN) DRV/r + RAL (ACTG 5262) DRV/r + RAL (NEAT 001)* ATV/r + RAL (HARNESS switch) MARAVIROC+ bpi (MARCH -Switch) * Strata high pvl and/or low CD4

9 Dual Therapy: Potential Boosted PI Regimens for Initial/Maintenance Therapy Study Treatment Setting N Regimen Results NEAT001 Initial 805 DRV/RTV + RAL Similar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high HIV-1 RNA, low CD4+ cell counts GARDEL Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs MODERN Initial 813 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + FTC/TDF SPARTAN Initial 94 ATV + RAL Similar virologic suppression, higher VF and hyperbilirubinemia rates vs ATV/RTV + FTC/TDF OLE Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART KITE Switch 60 LPV/RTV + RAL Small study; encouraging efficacy SALT Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs ATLAS-M Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs DUAL-GESIDA Switch 257 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 2 NRTIs Modified from Eron J and Sax P Slide credit: clinicaloptions.com

10 7 randomised trials of PI/r + RAL versus PI/r + 2NRTIs HIV RNA <50 copies/ml (switch = failure endpoint) Overall, in 7 randomised trials of 1266 patients, PI/r + raltegravir showed HIV RNA suppression rates 10% lower than PI/r + 2NRTIs (p=0.008). However there was evidence for heterogeneity between the trials (p=0.03). Favours 3-drug treatment Favours 2-drug treatment Courtesy Andrew Hill

11 Lamivudine Once daily NRTI Very well tolerated Almost no side effects reported No drug-drug interactions Generic, low cost Low genetic barrier, selects M184V or I Residual antiviral activity even after selecting the mutation Enhances antiviral activity of TDF and ZDV

12 Patients with HIV-1 RNA GARDEL: Viral load <50 copies/ml at weeks 48 and 96 (ITTe) 100% 90% 80% 70% Week 48 (p= 0.171, difference +4.6% [CI 95% : -2.2% to +11.8%]) 88.3% 90.3% 83.7% 84.4% <50 copies/ml (%) [1] 60% 50% 40% 30% 20% 10% Week 96 (p= 0.165, difference % [CI 95% : -2.3%; to 14.1 %]) 0% BSL W4 W8 W12 W24 W36 W48 W96 DT TT

13 Patients With HIV-1 RNA GARDEL: Viral load <50 copies/ml at weeks 48 and 96 (ITTe), baseline VL > 100,000 copies/ml < 50 copies/ml (%) [1] 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% W48 (p=0.145, difference +9.3% [CI 95% : -2.8% to +21.5%]) 87.2% 77.9% BSL W4 W8 W12 W24 W36 W48 W96 DT TT 90.7% 80.7% W96 (p=0.163, difference % [CI 95% : -3.8% ; 23.7 %])

14 OLE: Main endpoints 97.3% 97.3% 89.8% 90.1% 87.3% 87.6% Protocol defined VF Any blip Protocol defined VF or any blip Difference (95% CI) 0.05% (-5.3% to + 5.1%) Difference (95% CI) -0.25% (- 8.2 to + 7.6%) Difference (95% CI) 0.3% (- 8.5 to + 8.3%) Protocol defined VF: 2 consecutive VL>= 50 copies/ml; VF or any blip: any detectable VL >= 50 copies/ml

15 Atlas-M: ATV/r + 3TC non-inferior to ATV/r + 2 N(t)RTI-s

16 DUAL-GESIDA Switch study: DRV/RTV + 3TC Dual ART Noninferior to Triple ART at Wk 48 Pts (%) Stable regimen: DRV/r + TDF/FTC or ABC/3TC 2 months VL < 50 c/ml > 6 months HBs Ag (-) No resistance detected for 2 pts with resistance data in dual arm AE rates similar between arms D/c for AEs: 0.8% dual vs 1.6% triple ART (P =.55) Dual ART Triple ART Wk 48 difference: -3.8% (95% CI: -11.0% to 3.4%) Pts With 1, 2, or 3 Blips,* % Dual ART Triple ART P Value *Defined as transitory HIV-1 RNA 50 copies/ml in pts with HIV-RNA < 50 copies/ml at Wk Virologic Success 3 2 Virologic Nonresponse 8 6 No Virologic Data at Wk 48 Pulido F, et al. HIV Glasgow Abstract O331.

17 Patients, % ANDES: FDC of DRV/RTV+3TC was non-inferior to SOC DRV/RTV+TDF/3TC at 48 weeks % (95% CI, -7.5; 5.6) Primary outcome: VL<50 copies/ml at Week % (95% CI, -17.2; 14.4) -1.5% (95% CI, -0.9; 3.9%) Proportion of patients with plasma HIV-1 RNA < 50 copies/ml n= 136 n= 66 n= 70 ITT snapshot (n=145) n= 32 n= 12 n= 20 ITT snapshot, baseline VL >100,000 copies/ml (n=35) n= 136 n= 66 n= 70 Observed cases (n=140) Total 3DR 2DR Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, Abst. 489.

18 Dual Therapy: Potential InSTI-Based Regimens for Initial/Maintenance Therapy Regimen Treatment Setting Studies DTG + 3TC Initial PADDLE (open-label phase IV) ACTG A5353 (phase II) GEMINI 1/2 (randomized phase III) Maintenance ASPIRE (randomized phase III) DTG + RPV Maintenance SWORD 1/2* (randomized phase III) DTG + DRV/RTV Maintenance DUALIS (randomized phase III) DTG + ATV/RTV Maintenance DOLATAV (phase II) DTG + MVC Maintenance HP (single-arm phase III) RAL + ETR Maintenance ETRARAL

19 #W96 SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48 W < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < Not done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 70/<50 * < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 Not done < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < < 50 < 50 < 50 < 50 < 50 PDVF < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 <50 ITT-e: 90% < 50 copies/ml at W 48 & 96 Observed data: 95% <50 copies/ml n=1 with PDVF; No mutations detected Cahn: JIAS 2017 Virologic Outcome at Wk 24, n (%) [Primary endpoint] Success (pvl<50 copies/ml) Baseline HIV-1 RNA, copies/ml > 100,000 (n = 37) 100,000 (n = 83) Total (N = 120) 33 (89) 75 (90) 108 (90) Nonsuccess 3 (8) 2 (2) 5 (4) No data 1 (3) 6 (7) 7 (6) n = 3 with PDVF; n = 1 with emergent M184V and R263RK ITT-e: 90% < 50 copies/ml at W 24 Taiwo: CID 2018,

20 GEMINI-1 and -2 Phase III Study Design Identically designed, randomized, double-blind, parallel-group, multicenter, noninferiority studies Screening (28 d) 1:1 Double-blind phase Open-label phase Continuation phase ART-naive adults VL ,000 c/ml DTG + 3TC (N=716) DTG + TDF/FTC (N=717) DTG + 3TC Day 1 Week 24 Week 48 Week 96 Week 144 Eligibility criteria 10 days of prior ART No evidence of pre-existing viral resistance based on presence of any major resistanceassociated mutation No HBV infection or need for HCV therapy Primary endpoint at Week 48: participants with HIV-1 RNA <50 c/ml (ITT-E snapshot) a Countries Argentina Australia Belgium Canada France Germany Italy Republic of Korea Mexico Netherlands Peru Poland Portugal Romania Russian Federation South Africa Spain Switzerland Taiwan United Kingdom United States Baseline stratification factors: plasma HIV-1 RNA ( 100,000 c/ml vs >100,000 c/ml) CD4+ cell count ( 200 cells/mm 3 vs >200 cells/mm 3 ). a 10% noninferiority margin for individual studies. Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

21 HIV-1 RNA <50 c/ml % DTG + 3TC non-inferior to DTG + TDF/FTC at 48 weeks DTG + 3TC (N=716) DTG + TDF/FTC (N=717) < Study visit Adjusted treatment difference (95% CI) a DTG + TDF/FTC DTG + 3TC Percentage-point difference Pooled analyses supports noninferiority of DTG + 3TC versus DTG + TDF/FTC with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 GEMINI 1 & 2: Snapshot Analysis by Visit (Pooled) Cahn et al. AIDS 2018; Amsterdam, the Netherlands.-Abstr TUAB0106LB.

22 HIV-1 RNA <50 c/ml, % Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations Virologic outcome ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717) PP b DTG + 3TC (N=694) DTG + TDF/FTC (N=693) Adjusted treatment difference (95% CI) a DTG + TDF/FTC DTG + 3TC ITT-E PP Virologic success Virologic nonresponse No virologic data Percentage-point difference DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to proportion <50 c/ml at Week 48 (snapshot, ITT-E population) in both studies a Based on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA ( 100,000 c/ml vs >100,000 c/ml), CD4+ cell count ( 200 cells/mm 3 vs >200 cells/mm 3 ), and study (GEMINI-1 vs GEMINI-2). b PP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could potentially affect efficacy outcomes as determined by the medical monitor prior to database lock. Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

23 HIV-1 RNA <50 c/ml, % Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA: Snapshot Analysis Snapshot Analysis ,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 DTG + 3TC DTG + TDF/FTC 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/ml Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

24 HIV-1 RNA <50 c/ml, % Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot Analysis Snapshot Analysis ,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 DTG + 3TC DTG + TDF/FTC 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/ml Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

25 HIV-1 RNA <50 c/ml, % Without TRDF, % Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot and TRDF Analysis Snapshot Analysis TRDF Analysis ,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm ,000 >100,000 > Baseline HIV-1 RNA, c/ml Baseline CD4+ cell count, cell/mm 3 DTG + 3TC DTG + TDF/FTC 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/ml Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB, Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated) DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed) Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

26 Confirmed Virologic Withdrawals Through Week 48: ITT-E Population Low rates of virologic withdrawals were observed at Week 48 Variable, n (%) DTG + 3TC (N=356) GEMINI 1 GEMINI 2 Pooled DTG + TDF/FTC (N=358) DTG + 3TC (N=360) DTG + TDF/FTC (N=359) DTG + 3TC (N=716) DTG + TDF/FTC (N=717) CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1) Treatment-emergent resistance No treatment-emergent INSTI mutations or NRTI mutations were observed among participants who met CVW (confirmed virologic failure) criteria Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in plasma HIV-1 RNA of less than 1 log 10 c/ml by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/ml, or confirmed plasma HIV-1 RNA levels 200 c/ml on or after Week 24. Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to 200 c/ml after prior confirmed suppression to <200 c/ml.. Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

27 HIV-1 RNA <50 c/ml, % DTG + Rilpivirine is non-inferior to continuing ongoing ART in virologically suppressed patients Virologic outcomes Adjusted treatment difference (95% CI) a DTG + RPV (n=513) CAR (n=511) CAR DTG + RPV FDA label: For pts who have been virologically suppressed for 6 months and no history of treatment failure and no resistance to DTG or RPV Virologic success Inclusion criteria On stable CAR >6 months before screening 1st or 2nd ART with no change in prior regimen due to VF Confirmed HIV-1 RNA <50 c/ml during the 12 months before screening HBV negative <1 1 Virologic non-response 5 4 No virologic data Percentage-point difference DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48

28 Pts, Wk 96 (%) Dual therapy with Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART: 96-Wk Results (LATTE-2) Cabotegravir: InSTIs formulated as PO tablet and for long-acting IM injection LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309) Injectable Rilpivirine requires cold chain Virologic Success* *HIV-1 RNA < 50 copies/ml. Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate / AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2% ~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB 84 IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) PO CAB + ABC/3TC (n = 56) Virologic Non-response No Virologic Data Treatment Differences (95% CI) Q8W IM 10.0% Q4W IM 3.0% Eron J, et al. IAS Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].

29 % <50 Week 40 ANRS 167 LamiDol Study DTG/3TC Maintenance Subjects No Hx of failure, No Hep B 8 week Switch to 2NRTI+DTG 40 Weeks FU on DTG/3TC 1 x VF (no resistance) 4 SAE Suicidal ideation CK elevation post exercise Grade 4 Depression Acute Hep C 0 DTG+3TC Joly V, et al. 24th CROI; Seattle, WA; February 13-16, Abst. 458.

30 Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE) Virologic Outcomes at Week 48 (FDA Snapshot) 100,0% 90,0% 80,0% 70,0% 60,0% 50,0% 40,0% 30,0% 20,0% 10,0% 0,0% 90,9% 88,9% DTG+3TC 2,3% Cont ART 2,2% HIV-1 infected adults virologically suppressed on any 3-drug ARV regimen. CD4 nadir > 200 cells/mm3 No history of virologic failure 6,8% 8,9% HIV RNA <50 cpm HIV RNA >50 cpm No Virologic Data N On Study Taiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5.

31 Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE) Viral Blips Treatment Arm Week 0 Week 4 Week 12 Week 24 Week 36 Week 48 HIV RNA (cpm) DTG + 3TC <20 <20 191/<20 <20 <20 <20 Adherence Last missed dose (Participant Report) 1-2 wks ago HIV RNA (cpm) Cont ART <20 <20 351/<20 <20 <20 <20 Adherence Last missed dose 1-3 mo HIV RNA (cpm) Cont ART <20 <20 <20 <20 <20 179/30 Adherence Last missed dose 1-2 wks Past week HIV RNA (cpm) Cont ART <20 682/<20 <20 <20 <20 <20 Adherence Last missed dose >3 mo HIV RNA (cpm) Cont ART <20 <20 <20 Adherence Last missed dose >3 mo Taiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5. No resistance

32 What s New? DTG/RPV FDA Approved for Maintenance Therapy Once-daily single-tablet regimen of DTG and RPV First 2-drug STR FDA approved for use as a complete regimen in the US Indication Administration requirements Key DDIs Dose adjustments Key US Label Information For pts who have been virologically suppressed for 6 mos Pts must have no history of treatment failure and no resistance to DTG or RPV Must be taken with a meal Separate dose of DTG/RPV and antacid/polyvalent cation containing medications Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone None required for pts with mild/moderate renal impairment; in pts with CrCl < 30 ml/min, increase monitoring for AEs DTG/RPV [package insert]. November Slide credit: clinicaloptions.com

33 HIV-1 RNA <50 c/ml, % SWORD Studies: Snapshot Outcomes at Week 48 (Pooled) Virologic outcomes Adjusted treatment difference (95% CI) a DTG + RPV (n=513) CAR (n=511) CAR DTG + RPV Switching to DTG+RPV had a neutral effect on lipids, while significantly improving bone turnover biomarkers Virologic success a Adjusted for age and baseline 3 rd agent. <1 1 Virologic non-response 5 4 No virologic data Percentage-point difference DTG + RPV is non-inferior to CAR with respect to snapshot in the ITT-E population (<50 c/ml) at Week 48 Inclusion criteria On stable CAR >6 months before screening 1st or 2nd ART with no change in prior regimen due to VF Confirmed HIV-1 RNA <50 c/ml during the 12 months before screening HBV negative Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.

34 Mean serum concentration, µg/l Mean serum concentration, µg/l SWORD Study: RPV/DTG: Bone markers Bone Turnover Biomarkers: Change From Baseline to Week DTG + RPV CAR Baseline Week 48 Baseline Week 48 0, ,8 24,0 19,0 23,1 53,0 55,3 45,6 54,7 Osteocalcin P<0.001 a Procollagen 1 N-terminal propeptide P<0.001 a 15,9 12,9 16,2 17,1 Bone-specific alkaline phosphatase P<0.001 a 0,70 0,53 0,35 0,18 0,00 0,66 0,69 0,49 Type 1 collagen C-telopeptide P<0.001 a 0,63 a. P values are from an ANCOVA model adjusting for original ART third-agent class, age, sex, body mass index category, smoking status, and baseline biomarker level. Orkin C, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. BPD1/5.

35 95% pvl < 50 copies/ml (1pt with etravirine resistance IAS 2017, Abstr THPEB 542

36 Pts, Wk 96 (%) LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART Cabotegravir: INSTI formulated as PO tablet and for long-acting IM injection LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309) Virologic Success* *HIV-1 RNA < 50 copies/ml. IM CAB + RPV Q4W (n = 115) IM CAB + RPV Q8W (n = 115) PO CAB + ABC/3TC (n = 56) Virologic Nonresponse Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate / AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2% ~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB No Virologic Data Treatment Differences (95% CI) Q8W IM % Q4W IM % Eron J, et al. IAS Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].

37 SELECT (A5273): second-line LPV/r + RAL in resource-limited countries SELECT (A5273): Randomised, openlabel, phase 3, noninferiority study at 15 ACTG research sites in 9 resource-limited countries* ACTG, AIDS Clinical Trial Groups; NRTI, nucleoside reverse transcriptase inhibitor *Three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania, Thailand, and Zimbabwe Adapted from La Rosa et al. Lancet HIV June ; 3(6): e247 e258.

38 What about InSTIs monotherapy? Only tested with DTG Mixed results in regards to efficacy High rate of resistance selection in the integrase gene in case of VF Resistance mutations selected: 92Q; 97A; 118R; 140S; 148 K, R, H; 155H; 230R; 263K, among others 1,2. DTG monotherapy should not be used for initial therapy or as a simplification strategy 1. Wensing A et al: Topics in Antiviral Medicine (IAS-USA), Blanco Jl et al:curr Opin Infect Dis 2018

39 DTG Monotherapy after treatment for Primary HIV Infection Patients treated during primary HIV infection (within 180 days of acquiring HIV) may have lower reservoir compared to those treated with chronic infection Could these patients maintain suppression on DTG monotherapy? Study design: Continuation of cart Week 12 Week 24 Week 36 Week 48 N=103 Randomization 2:1 DTG vs cart Monotherapy Dolutegravir Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 36 Primary endpoint: Virological response, defined as proportion of patients without virological failure at week 48, or before Week 48 Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102B3.

40 Proportion of patients with virological response [%] DTG Monotherapy after treatment for Primary HIV Infection: Results 100% 80% 60% 40% 100% 100% 98,50% 100% 20% 0% 67/67 32/32 67/68 33/33 Pre-protocol DTG monotherapy Standard of care therapy (cart) Intention-to-treat Comparable slight decay of HIV-1 reservoir (cellular HIV DNA) and absence of CSF virus in both groups One patient with virologic failure in DTG mono arm (protocol violation - enrolled with chronic HIV and higher HIV reservoir) Results suggest that simplification strategies may require stratification for appropriate candidates Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102.

41 Moncay study: switch to DTG monotherapy vs remain on ABC/3TC/DTG Open-label, randomized, controlled trial in 9 reference centers in France Stable, efficient and well-tolerated DTG/ABC/3TC regimen* Randomization 1:1 (n=158) DTG/ABC/3TC single tablet QD (n=80) DTG 50 mg QD (n=78) Screening ** Baseline Week 24 Week 48 Non-inferiority margin: 12% Primary endpoint: proportion with pvl <50 c/ml in ITT, mitt and PP analyses (with a pre-planned non-inferiority margin of 12%); virologic failure (VF) = 2 consecutive pvl >50 c/ml; ITT, missing or switch = failure (M=F) Secondary endpoints: changes in CD4 count, CD4:CD8 ratio, egfr, lipids; HIV-DNA and genital sub-studies * HIV-RNA (pvl) <50 c/ml for >12 months, no AIDS event (except past tuberculosis), nadir CD4 >100/mm 3, no mutation to or failure on any INSTI-based regimen ** pvl < local threshold (20 to 40 c/ml) Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.

42 HIV-1 RNA <50 c/ml, % Moncay study: 24 week results Virologic outcomes (ITT) W24 treatment difference DTG/ABC/3TC (n=80) TC/DTG arm 95% Risk difference (95% CI) Confidence DTG better DTG/ABC/3TC better Interval 60 DTG (n=78) 7/80 (96.3%) [-5 to 10.8] 40 7/78 (98.7%) [-4.5 to 8.1] 20 0 Virologic success Virologic non-response No virologic data 6/77 (98.7%) [-4.5 to 8.8] Virologic success (%) difference DTG was non-inferior to DTG/ABC/3TC at Week 24 with respect to snapshot in the ITT, mitt and PP population Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.

43 VF-Free Survival (%) Moncay study : extended follow up P=0.005 (Log-Rank Test) Time in Weeks DTG/ABG/3TC arm DTG arm Similar results in DOMONO trial of DTG maintenance monotherapy: Noninferior virologic suppression at Wk 24, unacceptable VF afterward [3 Excess virologic failures in DTG monotherapy arm led to DSMB recommendation to stop the study 2/7 study subjects with virologic failure developed resistance to DTG (1 pt with S147G, N155H, another with R263K) Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.

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45 What Data Are Needed to Change the Treatment Paradigm of HIV Therapy? Well-designed noninferiority trials vs triplecombination therapy With a clear definition of treatment success and failure Sufficient number of patients in new strategies Robust risk assessment (for both the individual patient and for public health concerns) Criteria for identification of patients who are likely to succeed/benefit from new strategies Assessment of response durability on experimental arm

46 Dual therapy: Remaining questions How would dual therapy perform in the context of PW, TB co-treatment, Hepatitis B, adolescents, and children? What are the pragmatic issues related to having patients on both three-drug and twodrug regimens? - How do we balance the financial impact of dual therapy with treatment durability in lowresource settings?

47 The future of dual therapy Reverse transcriptase inhibition seems to be crucial for DT The anchor drug must have high genetic barrier DT can be safely prescribed in virologically suppressed patients, with no previous failure So far, DT is only considered as alternative option in naive pts If the results of ongoing trials are sustainable, a new paradigm for first line treatment and early switch might be generated. In the era of Test & Treat, DT could be a first line preferred strategy, with minimal monitoring requirements, leaving future treatment options in case of failure, as only M184V (or NNRTI) mutations would be expected to emerge. This could be an important contribution to the 90/90/90 targets.

48 Thank you for your attention