2Dr : Lessons Learned, Challenges Ahead

2DR : LESSONS LEARNED, CHALLENGES AHEAD

Professor Chloe Orkin Queen Mary University of London Barts Health NHS Trust CONFLICTS OF INTEREST – PROF. CHLOE ORKIN

• I have received: • Honoraria for lectures and advisory boards • Travel grants • Research grants to my institution • From Gilead Sciences, Janssen, MSD and ViiV Healthcare DO WE NEED 3 DRUGS FOR THE WHOLE OF LIFE?

Age 20 Age 100 WE NOW HAVE 2DR FIXED DOSE COMBINATIONS

TDF/FTC/RFVTDF/FTC/EFV DTG/3TC TDF/FTC/RPV DTG/RPV

TAF/FTC/BIC TDF/FTC/EVG/COBI

TAF/FTC/DRV/COBI ABC/3TC/DTG

TAF/FTC/RPV TAF/FTC/EVG/COBI

TDF/3TC/DOR NO 2DR FOR PEOPLE WITH CHRONIC HEPATITIS B (SAG+)

HIV

CHRONIC HEPATITIS B

Lancet HIV. https://doi.org/10.1016/S2352-3018(19)30342-X DTG/3TC IN GUIDELINES- FIRST LINE ART DHHS • Recommended Initial Regimens for Most People with HIV EACS • Recommended regimen

NOT YET IN IAS-USA OR WHO GUIDELINES

DHHS Guidelines. December 2019. EACS Guidelines 10.0 November 2019 DTG/3TC RESTRICTIONS-FIRST LINE ART

HBsAg+ CD4 < 200 HIV RNA > 500,000 No baseline genotype DHHS EACS

DHHS Guidelines. December 2019. EACS Guidelines 10.0 November 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211994s000lbl.pdf https://www.ema.europa.eu/en/documents/product-information/dovato-epar-product-information_en.pdf EVIDENCE FOR DTG + 3TC IN TREATMENT-NAÏVE PATIENTS…

Efficacy, safety and durability?

What about more sensitive viral markers i.e. target not detected?

Is the frequency of blips the same with DTG + 3TC versus DTG-based 3DR?

Are the rate of and time to virologic suppression the same?

Is the barrier to resistance of DTG + 3TC high enough?

Safety and tolerability? LONG-TERM DURABILITY: DTG + 3TC IS NON-INFERIOR TO DTG + TDF/FTC IN SNAPSHOT HIV-1 RNA <50 C/ML AT WEEK 96 (GEMINI-1 AND -2)

100 93,4 93,3 87,0 89,4 89,5 93,2 91,5 Snapshot 80 72,0 87,2 84,4 86,0 70,2 60 Responders, Adjusted difference, Treatment n/N (%) % (95% CI)* 40 DTG + 3TC 616/716 (86.0) −3.4 (−6.7, 0.0) Snapshot DTG + TDF/FTC 642/717 (89.5) 1 RNA <50 c/mL,RNA CI)(95% 1 % - 20 DTG + 3TC 692/716 (96.6) 0.2 (−1.8, 2.2)

HIV TRDF DTG + TDF/FTC 691/717 (96.4) 0 0 4 8 12 16 24 36 48 60 72 84 96 Study visit, week • Non-inferiority criteria were met for GEMINI-1, GEMINI-2 and the pooled analysis†

• TRDF population accounts for confirmed virologic withdrawal, withdrawal due to lack of efficacy, withdrawal due to treatment-related AEs and patients who met protocol-defined stopping criteria

*Based on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL), CD4+ T-cell count (≤200 vs >200 cells/mm3) and study (GEMINI-1 vs GEMINI-2). The upper limit of the 95% CI for the pooled analysis was 0.0007%. TRDF (unadjusted difference) was a pre-planned analysis at Week 96; †In GEMINI-1, HIV-1 RNA <50 c/mL (95% CI) was achieved in 300/356 patients (84.3% [80.5, 88.1]) in the DTG + 3TC group and 320/358 (89.4% [86.2, 92.6]) in the DTG + TDF/FTC group (adjusted treatment difference [95% CI], −4.9% [−9.8, 0.03]). In GEMINI-2, the corresponding values were 316/360 (87.8% [84.4, 91.2]) and 322/359 (89.7% [86.5, 92.8]), respectively (adjusted treatment difference [95% CI], −1.8% [−6.4, 2.7]) Cahn P, et al. IAS 2019. Oral WEAB0404LB AE, adverse event; CI, confidence interval; TRDF, treatment related discontinuation=failure Cahn P, et al. J Acquir Immune Defic Syndr 2020;83:310–8 GEMINI :HIV-1 RNA <50 C/ML AT WEEK 96 BY BASELINE VL SUBGROUPS

100 90 90 87 86 84 83 80 78 80 80 75 69 70

50 DTG + 3TC 40

1 RNA <50 c/mL,RNA1 % DTG + TDF/FTC -

HIV 30

10 499/ 510/ 117/ 132/ 41/ 38/ 14/ 18/ 9/ 12/ 576 564 140 153 51 46 18 24 13 15 0 ≤100,000 >100,000 >250,000 >400,000 >500,000 Baseline VL strata - HIV-1 RNA, c/mL

Adapted from van Wyk J, et al. ID Week 2019. Slides 2842 Cahn P, et al. J Acquir Immune Defic Syndr 2020;83:310–8 WEEK 96 SNAPSHOT ANALYSIS - BASELINE CD4+ COUNT <200 CELLS/MM3

2DR study 3DR study

100 94 90 86 87 81 83 82 80 78 78 73 71 73 72 68 68 70 65 62 60 56 58

1 RNA <50 c/mL, 1 RNA % 40 HIV - 30

10 n 39 45 39 28 18 14 26 28 32 38 26 32 26 34 43 48 N 57 62 55 50 23 24 32 36 34 44 NR NR 40 39 36 55 63 55 0 DTG + ABC/3TC EFV/FTC/TDF DTG + RAL + 2NRTIs DTG/ABC/3TC ATV/r + FTC/TDF DTG/ABC/3TC BIC/F/TAF DTG + FTC/TAF BIC/F/TAF D/C/F/TAF D/C + F/TDF DOR/3TC/TDF EFV/FTC/TDF DOR + 2 NRTIs DRV/r + 2NRTIs DTG + 3TC DTG + FTC/TDF DTG + EFV/ DTG2NRTIs + RAL + DTG/ DRV/r + DTG/ BIC/ DTG + BIC/F D/C/ D/C + DOR/ EFV/ DOR + 2 DRV/r + DTG + DTG + ABC/ FTC/ 2NRTIs 2NRTIs ABC/ FTC/ ABC/ FTC/ FTC/TAF TC/ FTC/ FTC/ 3TC/ FTC/ NRTIs 2 NRTIs 3TC FTC/TDF 3TC TDF 3TC TDF 3TC TAF TAF TAF TDF TDF TDF

SINGLE1 SPRING-21 FLAMINGO1 GS-14892 GS-14903 AMBER4 DRIVE-AHEAD*5 DRIVE-FORWARD*†6 GEMINI-1 and -2*7

*Studies present ≤200 cells/mm3 (rather than <200) Adapted from: 1. Granier C, et al. CROI 2015. Poster 550; 2. Wohl D, et al. Lancet HIV 2019;6:e355–63 Supplementary Appendix †Observed failure approach 3. Stellbrink H, et al. Lancet HIV 2019;6:e364–72 Supplementary Appendix; 4. Orkin C, et al. HIV Glasgow 2018. Oral O212 NR, not reported 5. Orkin C, et al. ID Week 2018. LB1; 6. Molina JM, et al. IAS 2018; 7. Cahn P, et al. IAS 2019. Oral WEAB0404LB GEMINI : SENSITIVE VIRAL MARKERS WEEK 96

Proportion of participants with TND by visit (Snapshot analysis, ITT-E population) DTGDTG + 3TC3TC; (N=716) N=716 100%100 DTGDTG + TDF/FTCTDF/FTC; (N=717) N=717 90%90 77%77 80%80 73%73 73%73 70%70 69%69 68%68 69%69 68%68 66%66 66%66 68%68 70%70 65%65 63%63 65%65 60%60 59%59 60%60 57%57 56%56 52%52 49%49 50%50

40%40 34%34 32%32

Proportion, % 30%30 20%20 10%10 0%0 44 8 1212 1616 2424 36 48 6060 72 8484 9696 Week

Number at base of bars is number of participants reaching TND at week visit ITT-E, intention-to-treat exposed; TD, target detected; TND, target not detected Underwood et al. EACS 2019; Basel, Switzerland. Slides PS8/2 GEMINI BLIP FREQUENCY WEEK 48

• Similar frequencies of blips were observed across arms by week of visit • No patients with CVW in either arm had blips prior to CVW • Cumulative occurrences: DTG + 3TC n=87; DTG + TDF/FTC n=109

3,8 4 3,6 DTG + 3TC (N=716*) 3,5 3,3 2,9 3 2,7 2,8 DTG + TDF/FTC (N=717*) 2,5 2,5 2,2 2,2 1,9 2 1,3 1,5 1,2 1 0,5 14 14/ 12 24 19 22 18 26 15 15 9/ 8/

Proportion with with blips, Proportion %* n / 496 / / / / / / / / 67 69 0 51 62 63 65 65 71 72 67 68 8 1 Week7 8 Week5 2 12 Week7 916 Week4 624 Week4 336 Week 48

A ‘blip’ is defined here as VL of 50-<200 c/mL with adjacent values <50 c/mL *Percentages were calculated from number of blips using previously suppressed (<50 c/mL) patient numbers, respectively, for DTG + 3TC and DTG + TDF/FTC at Week 8 (n=517) and (n=496); Week 12 (n=625) and (n=632); Week 16 (n=657) and (n=659); Week 24 (n=714) and (n=726); Week 36 (n=674) and (n=683); and Week 48 (n=678) and (n=691). Bold numbers on chart are number of blips at given week visits. Individual patients can have had more than one blip CVW, confirmed virologic withdrawal Adapted from Underwood M, et al. IAS 2019. MOPEB231 RATE OF, AND TIME TO, VIROLOGIC SUPPRESSION : GEMINI

Overall study population Participants with baseline HIV-1 RNA (all participants)1,2 >100,000 c/mL2 0 0 DTG + 3TC DTG + TDF/FTC –-11 –-11 c/mL 10

–-22 –-22 1 RNA,1 log - –-33 –-33 HIV

–-44 0 –-44 0 Mean change from baseline in in baseline plasma from change Mean -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Weeks Weeks

DTG + 3TC, n 716 708 704 686 681 688 674 664 140 138 139 135 135 138 132 132 DTG + TDF/FTC, n 717 706 699 699 688 688 681 675 153 152 153 151 149 145 141 139

Adapted from: 1. Cahn P, et al. Lancet 2019;393;143–155 Supplementary Appendix 2. Eron J, et al. HIV DART and Emerging Viruses 2018. Oral 7 RESISTANCE BARRIER GEMINI STUDIES

GEMINI-1 GEMINI-2 Pooled

DTG + DTG + DTG + DTG + DTG + DTG + 3TC TDF/FTC 3TC TDF/FTC 3TC TDF/FTC (N=356) (N=358) (N=360) (N=359) (N=716) (N=717) Variable, n (%)

Week 48 CVW 4 (1.1) 2 (0.6) 2 (0.6) 2 (0.6) 6 (0.8) 4 (0.6)

Week 96 CVW 5 (1.4) 4 (1.1)* 6 (1.7) 3 (0.8) 11 (1.5) 7 (1.0)*

Treatment-emergent resistance 0 0 0 0 0 0

*One participant met the criteria for CVW at Week 12 but was not reported at the Week 48 analysis because of a laboratory reporting error identified after the Week 48 analysis Adapted from Cahn P, et al. IAS 2019. Oral WEAB0404LB GEMINI WEEK 96 - AE PROFILES WERE SIMILAR LOWER RISK OF DRUG-RELATED AES IN THE DTG + 3TC GROUP AT WEEK 96

• Increased weight was reported as an AE in 13 (1.8%) patients treated with DTG + 3TC and in 10 (1.4%) treated with DTG + TDF/FTC • Overall mean change from baseline was 3.1 kg in the DTG + 3TC group and 2.1 kg in the DTG + TDF/FTC group DTG + 3TC DTG + TDF/FTC n (%) (N=716) (N=717) Any AE 591 (83) 609 (85) AEs occurring in ≥10% of patients in either group Nasopharyngitis 71 (10) 114 (16) Diarrhoea 89 (12) 93 (13) Headache 79 (11) 87 (12) Drug-related AEs* 140 (20) 179 (25) Any Grade 2–5 drug-related AEs 50 (7) 57 (8) Grade 2–5 drug-related AEs occurring in ≥1% of patients Headache 8 (1) 8 (1) AEs leading to withdrawal from the study 24 (3) 23 (3) AEs of interest leading to withdrawal from the study Neuropsychiatric 10 (1) 5 (1) Renal-related 2 (<1) 7 (1) Osteoporosis 0 2 (<1) Any serious AE† 64 (9) 67 (9)

*Relative risk (95% CI) for the DTG + 3TC versus DTG + TDF/FTC group was 0.78 (0.64, 0.95) †3 deaths (acute myocardial infarction, n=1; Burkitt’s lymphoma, n=1; coronary artery disease, n=1), 1 in GEMINI-1 and 2 in Adapted from Cahn P, et al. IAS 2019. Oral WEAB0404LB GEMINI-2; all were in the DTG + 3TC group and were considered unrelated to the study drug regimen Cahn P, et al. J Acquir Immune Defic Syndr 2020;83:310–8 CHANGE IN RENAL BIOMARKERS AT WEEK 96 FAVOURS DTG + 3TC

DTG + 3TC (N=716) Plasma/serum markers *p<0.001 Urine markers **p<0.005 DTG + TDF/FTC (N=717) ** * 15.4 * 1616 12,3 ‡ 6060 50.8 10,7 ‡ * 1212 8,8 5050 88 4040 35.0 † † 44 * 3030 00 2020 * 16.2 --44

baseline 1010 3.2 --88 00

from baseline --1212 --1010 --1616 Change from baseline, % baseline, from Change Adjusted Adjusted mean change -14.6 Adjusted mean change from from mean change Adjusted --2020 -12.2 --2020 -18.2 Change from baseline, % -18.7 --3030 Creatinine GFR from GFR from Protein/Protein/ RetinolRetinol-binding-binding BetaBeta-2 -2 Creatinine(µmol/L) GFRcreatinine, from GFRcystatin from cystatin C, C, creatinine protein/ microglobulin/ (μmol/L) creatinine,CKD-EPI CKD -EPI CKDCKD-EPI-EPI creatinine(g/mol) creatinineprotein macroglobulincreatinine (mL/min/1.73 m2)2 (mL/min/ 2 (g/mol) (µg/mmol)creatinine (mg/mmol)creatinine (mL/min/1.73 m ) (mL/min/1.732 m ) 1.73 m ) (μg/mmol) (mg/mmol)

• Renal AEs leading to discontinuation were comparable across both arms (DTG + 3TC: n=2, <1%; DTG + TDF/FTC: n=7, 1%)

†Estimated mean change from baseline in each group was calculated from a repeated measures model adjusting for study, treatment, visit, baseline plasma HIV-1 RNA, baseline CD4+ T-cell count, age, sex, race, presence of diabetes mellitus, presence of hypertension, baseline biomarker value, treatment and visit interaction, and baseline biomarker value and visit interaction. No assumptions were made about the correlations between participant readings of biomarkers (the correlation matrix for within-participant errors was unstructured) ‡ Estimated from geometric means ratio for baseline and Week 96. Based on the same model as plasma/serum markers except adjusting for loge-transformed baseline biomarker (continuous) Adapted from Cahn P, et al. IAS 2019. Oral WEAB0404LB CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate Cahn P, et al. J Acquir Immune Defic Syndr 2020;83:310–8 GEMINI CHANGE IN BONE BIOMARKERS AT WEEK 96 FAVOURS DTG + 3TC * *p<0.001 2525 23,7

† 2020

151 5 11,0 101 * 0

from µg/Lbaseline, from * Adjusted change mean Adjusted 4,21 * 55 2,36 0,29 0,27 0,10 0,24 00 SerumSerum bone-specificbone-specific Serum SerumSerum procollagen procollagen 11 SerumSerum type type 1 1 collagen collagen alkalinealkaline phosphatasephosphatase osteocalcinosteocalcin N-terminalN-terminal propeptide propeptide C-telopeptideC-telopeptide

DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

• DTG/3TC • DTG/RPV

• LPV/b + 3TC • ATV/b + 3TC Boosted • DRV/b +3TC • DRV/b + DTG SUMMARY FINDINGS-BPI 2DR META-ANALYSIS 7 TRIALS (N=~1600)

100 83.6% 80.6% 90 Dual Triple 80 70 60 50 40

endpoint ( endpoint %) 30 Dual Triple Triple 20 Dual Dual Triple 5.0% 4.5% 2.4% 3.6% 10 0.7% 0.7%

Percentage of patients who achieved achieved who patients of Percentage 0 <50cp/mlHIV-RNA <50 ProtocolPDVF Defined ResistanceResistance DiscontinuationsD/AE copies/mL Virological Failure Mutations due to adverse events Liew HIV Glasgow 2018 AbstrO144 DTG/3TC IN GUIDELINES SWITCH

DHHS • Good option if no resistance to either drug and no HBV coinfection EACS • Dual therapies supported by large randomized clinical trials or meta-analyses

DHHS Guidelines. December 2019. EACS Guidelines 10.0 November 2019 DTG/3TC IS NON-INFERIOR TO TAF-BASED REGIMENS AT WEEK 48

Virologic outcomes Adjusted treatment difference (95% CI)† 100100 93,2 93,0 DTG/3TC TAF-based regimen DTG/3TC 8080 (N=369) 0.7 Primary endpoint: –1.2 DTG/3TC non-inferior to TAFTAF-based-based regimen 4% non- TAF-based regimen 6060 (N=372)regimen (N=372) -0,3 inferiority (≥50 c/mL) at Week 48 margin –8 –6 –4 –2 0 2 4 6 8 4040 -8 -6 -4 -2 0 2 4 6 8 TAF-based regimen DTG/3TC

2020 Key secondary endpoint:

Proportion of of % Proportion participants, 6,5 6,5 -3.4 3.9 DTG/3TC non-inferior to 0,3 0,5 -8% non- TAF-based regimen 00 inferiority 0,2 (<50 c/mL) at Week 48 HIVHIV-1 RNARNA HIV-1HIV-1 RNA NoNo virologicvirologic margin ≥50≥50 c/mL* c/mL <50<50 c/mL datadata -8–8 –-66 –-44 –-22 0 2 44 66 88 Adjusted difference, %

• In the per-protocol population, 0/352 participants in the DTG/3TC group and 2/358 participants in the TAF-based regimen group had HIV-1 RNA ≥50 c/mL at Week 48 (adjusted difference, −0.6; 95% CI, −1.3 to 0.2)†

*Primary endpoint (Snapshot virologic non-response, ITT-E) †Based on Cochran-Mantel-Haenszel stratified analysis adjusting for baseline third agent class van Wyk J, et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB CI, confidence interval van Wyk J, et al. Clin Infect Dis 2020 [Epub ahead of print] SUMMARY OF PROPORTION OF PARTICIPANTS WITH HIV-1 RNA <40 C/ML AND TND, <40 C/ML AND TD, AND ≥40 C/ML BY VISIT

• The proportion of participants with VL <40 c/mL and TND per visit through Week 48 was high and similar in both treatment arms

Note: Denominator n at each visit is number of participants with available viral load data within the visit window.

Wang et al. AIDS 2020: Virtual. Slides PEB0238. 26 >2,000 PLHIV WORLDWIDE HAVE RECEIVED DTG + 3TC* IN REAL- WORLD, SUPPRESSED SWITCH STUDIES†

See Europe – detailed view

1 4 5

6 9 10 7 8

12 11

Numbers correspond to references. Figure is accurate to the level of country of study, placement within country is for visual representation purposes only. Potential overlap between patient cohorts cannot be ruled out *Includes patients treated with DTG + 3TC in accordance with the DOVATO EU SmPC13; †Note that for some studies, a small number of patients were not suppressed at baseline2,8–12 SmPC, summary of product characteristics See slide notes for references VIRAL FAILURE

• Results showed that, at W48, there were 1.3% (95% CI: 0.6, 2.1) viral failures for DTG+3TC regimen in the random effects model. At W96 analysis, 2.0% (95% CI: 0.9, 3.5) viral failure was reported for the DTG+3TC regimen in random effects analysis

• No study reported presence of treatment emergent resistance

Punekar et al. AIDS 2020: Virtual. Poster PDB0103. 28 DTG/RPV IN GUIDELINES SWITCH DHHS • Reasonable option when the use of nucleoside reverse transcriptase inhibitors is not desirable EACS • Dual therapies supported by large randomized clinical trials or meta-analyses

DHHS Guidelines. December 2019. EACS Guidelines 10.0 November 2019 DTG/RPV IN SWITCH KNOWNS • Durability (3 years) • Virological suppression < 50 (TND) = 3DR • Slightly increased (0.6% of SWORD participants) risk of resistance (NNRTI not ISTI) • Improvement bone/renal biomarkers (vs TDF) • No consistent changes in inflammatory biomarkers UNKNOWNS • Impact of archived resistance, especially M184V • Pregnancy • Long term weight changes

Aboud M et al. The Lancet HIV 2019; 6:e576–e587. Orkin et al C 25th BHIVA P008. Underwood M et al HIV Drug Therapy Glasgow 2018 P311

LA AND 2DR POTENTIAL

Entry fusion bNAb NRTI/NRTTI NNRTI Integrase Protease Capsid Maturation TLR 7 inhibitor inhibitor inhibitor inhibitor inhibitor agonist

Albuvirtide UB-421 Islatravir Elsulfavirine RAL LA ATV LA IM Lenacapavir GSK937 Vesatolimod

Leronlimab ACC007 PRO-140 TAF implant CAB LA RTV LA IM VRC 01/LS VRC 07/LS RPV LA PG121 + Elipovimab MK8507 8 | Maturation 3BNC117 LS + 10-1074 LS

10-1074 2 | Fusion 3 | Reverse transcription

HIV LIFE CYCLE QUESTIONS [email protected] @profchloeorkin