Report Back: HIV Treatment Updates

Report Back: HIV Treatment Updates Catherine Koss, MD Assistant Professor Division of HIV, Infectious Diseases, and Global Medicine Zuckerberg San Francisco General Hospital University of California, San Francisco

Outline 1. Global AIDS epidemic 2. SEARCH and Ya Tsie (BCPP) trials 3. Peri-conceptional dolutegravir and risk of neural tube defects 4. DTG + 3TC in ART-naïve patients 5. Dolutegravir monotherapy 6. Doravirine 7. DTG BID vs EFV in TB co-infection

2014: UNAIDS established 2020 Fast-Track targets to create momentum to end AIDS as a public health threat by 2030 90-90-90 targets 90% of PLHIV know their status 90% on treatment 90% virally suppressed (overall 73% population-level viral suppression) <500,000 new HIV infections <500,000 AIDS-related deaths

2017: 36.9 million adults and children living with HIV and 21.7 million on ART Millions of People 40 35 30 25 20 15 10 5 0 36.9 Million 21.7 Million 17.5 Million 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 PLHIV Receiving ART Virally suppressed Only half of children <15 years are on ART Source: UNAIDS, 2018 Source: UNAIDS 2018 estimates; Baral S. AIDS 2018 Plenary.

Number of global AIDS-related deaths has declined but not on track 3 000 000 AIDS-related deaths in 2017 Total 940 000 [670 000-1.3 million] Adults 830 000 [590 000-1.2 million] Children (<15 y) 110 000 [63 000-160 000] 2 500 000 Number of AIDS-related deaths 2 000 000 1 500 000 1 000 000 500 000 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 AIDS-related deaths Target Source: UNAIDS 2018 estimates.

UNAIDS: Prevention crisis New HIV infections in 2017 Total 1.8 million [1.4 million-2.4 million] Adults 1.6 million [1.3 million-2.1 million] Children (<15 y) 180 000 [110 000-260 000] Number of new HIV infections, global, 1990 2017 and 2020 target 5 000 000 4 500 000 4 000 000 Number of new HIV infections 3 500 000 3 000 000 2 500 000 2 000 000 1 500 000 1 000 000 500 000 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 New HIV infections Target Source: UNAIDS 2018 estimates.

Global progress toward 90-90-90 75% [55 92%] 79% [59 >95%] 81% [60 >95%] of people living with HIV know their status of people living with HIV who know their status are on treatment Global HIV testing and treatment cascade, 2017 40 of people on treatment are virally suppressed U.S. HIV care continuum, 2015 Number of people living with HIV (million) 30 20 10 75% [55 92%] 59% [44 73%] 47% [35 59%] 73% 0 People living with HIV who know their status People living with HIV on treatment People living with HIV who are virally suppressed UNAIDS special analysis 2018. https://www.cdc.gov/hiv/pdf/library/factsheets/ cdc-hiv-care-continuum.pdf

Disclosure: I am a SEARCH co-investigator. Havlir D, et al. AIDS 2018. WEAX0106LB

90-90-90 targets exceeded within 2 years in intervention communities Proportion ever tested for HIV ART start among HIV+ not on ART at baseline Viral suppression among all PLHIV Ramp up in HIV testing coverage in both arms from 57% pre SEARCH to 90% after baseline testing More rapid ART start in all CD4 strata in intervention communities Year 3 viral suppression 11% higher (p<0.001) in intervention vs. control Year 3 viral suppression in intervention: women (81%), men (74%), youth (55%) Havlir D, et al. AIDS 2018. WEAX0106LB

Improved Community Health 21% HIV mortality 59% TB incidence yr 3 in BL HIV+ 26% HTN control Reduced HIV Incidence 32% Annual HIV incidence within intervention arm Cumulative HIV incidence between arms* * Active control arm 90% HIV testing coverage at baseline, rapid adoption of expanded ART eligibility guidelines (CD4 <350 to <500 and Option B+) SEARCH multi-disease, patient-centered approach is one model that can be adapted in rural Africa to accelerate reductions in mortality, TB and new HIV infections synergistically with improved NCD control -- in line with UN Sustainable Development Goals. Need additional strategies to achieve HIV elimination (<0.1% incidence): innovative models for youth combination prevention (e.g. PrEP, VMMC, vaccine) Havlir D, et al. AIDS 2018. WEAX0106LB

Ya Tsie: Botswana Combination Prevention Project (BCPP) Botswana: ~25% prevalence High coverage of testing and ART Pair-matched community randomized trial evaluate population-level impact of treatment + prevention interventions in 15 intervention/15 control communities Interventions Home-based and mobile HIV testing + targeted testing Comprehensive linkage to care + active tracing Fast-track expanded ART start (vs. country standard CD4 <350) Botswana transitioned to universal ART in June 2016 Baseline and annual surveys in random sample of 20% of households in all 30 communities to evaluate HIV incidence Makhema MJ et al. AIDS 2018. WEAX0105LB

Intervention Coverage by Randomization Arm, baseline vs study end (from 6 End of Study communities, 3 pairs) 100 HIV Testing ART in all HIV+ VL<400 in all HIV+ 95 90 85 86% 84% 88% 92% 85% 90% 82% 88% 80 75 70 76% 72% 75% 70% Standard of Care Intervention 65 Knew HIV+ status, baseline Knew HIV+ status, study end On ART, baseline On ART at study end VL suppression, baseline VL suppression at study end 18% greater viral suppression in intervention arm (baseline vs end of study) 7% greater viral suppression in standard of care arm (p<0.0001) Intervention arm: 88% of all persons identified with HIV had undetectable viral load Makhema MJ et al. AIDS 2018. WEAX0105LB 13

Ya Tsie (BCPP) Primary Results: HIV Incidence in the Intervention vs. Standard of Care Arms Annualized HIV incidence: Intervention arm: 0.59% Standard of care arm: 0.92% Analysis Primary analysis (permutation test, pair specific Cox PHM), unadjusted Analysis to obtain 95% CI (standard pair stratified Cox PHM), unadjusted Incidence Ratio 95% CI 2 sided p value 0.69 0.09 0.65 0.46 0.90 0.01 Primary analysis, adjusted* 0.62 0.04 Analysis to obtain 95% CI, adjusted* 0.70 0.50 0.99 0.04 * Adjusted for: sex, age, education, marital status, concurrent sexual partners, and alcohol during last sex Results of main analyses are consistent, and indicate at least a 30% reduction in HIV incidence associated with the intervention Makhema MJ et al. AIDS 2018. WEAX0105LB

Peri-conceptional dolutegravir and risk of neural tube defects Tsepamo: surveillance study evaluating birth outcomes by HIV and ART status (~45% of births in Botswana) Botswana switched from EFV to DTG as first-line ART in 2016 Neural tube closes 28 days after fertilization (6 weeks post-lmp) NTDs caused by folate deficiency, drugs (e.g. valproic acid), familial

NTD Prevalence by HIV status and ART Exposure PERCENTAGE (95% CI) WITH NEURAL TUBE DEFECT 2.5 2 1.5 1 0.5 0 0.94 DTG CONCEPTION 0.12 ANY NON DTG ART CONCEPTION 0.05 EFV CONCEPTION 0.00 DTG STARTED DURING PREGNANCY 0.09 HIV NEG NTDs/ Exposures 4/426 14/11,300 3/5,787 0/2,812 61/66,057 % with NTD (95% CI) Prevalence Difference (95% CI) 0.94% (0.37%, 2.4%) ref Updated data through July 15, 2018 DTG exposure at conception: 4/596 (0.67%, 95% CI 0.26%, 1.7%) - 95% CI does not overlap with any other exposure group 0.12% (0.07%, 0.21%) -0.82% (-0.24%, -2.3%) 0.05% (0.02%, 0.15%) -0.89% (-0.31%,- 2.3%) 0.00% (0.00%, 0.13%) -0.94% (-0.35%, -2.4%) 0.09% (0.07%, 0.12%) -0.85% (-0.27%, -2.3%) 1. Zash R, et al. N Engl J Med. 2018. 2. Zash R, et al. AIDS 2018. Session TUSY15.

Four distinct NTDs - DTG at conception Anencephaly Myelomeningocele (+ undescended testes) Encephalocele Iniencephaly (+ major limb defect) None of women were on folate supplementation prior to pregnancy Botswana does not fortify grains with folate No other risk factors for NTD identified Family history not collected Moore C. AIDS 2018. Session WESY11. Mofenson, L and Zash R, et al. AIDS 2018. Session TUSY15.

Additional birth outcomes data anticipated Tsepamo study expanded to include 72% of national births Next formal analysis in March 2019 will include ~1226 births with exposure to DTG from conception 0 additional NTDs, the lower bound of CI (0.13%) overlaps with upper CI for other ART at conception (0.21%) EFV at conception (0.15%) and HIV uninfected (0.13%) 1 additional NTD, the lower bound of CI (0.18%) overlaps with the upper CI for other ART at conception (0.21%) Zash R, et al. AIDS 2018. Session TUSY15.

What do guidelines recommend? Use of dolutegravir among women Currently Receiving DTG? No Yes DTG may be used Use DTG or another option Do not use DTG Pregnancy Status Early pregnancy* Late pregnancy Childbearing potential, no contraception Childbearing potential, effective contraception Early pregnancy* Late pregnancy Childbearing potential, no contraception Childbearing potential, effective contraception *DHHS: < 8 wks from last menstrual period; BHIVA and WHO: first trimester. Recommendation on DTG DHHS [1] BHIVA [2] WHO [3] DHHS Guidelines: Discontinuing DTG-based regimens is unlikely to confer any benefits after the neural tube has formed, and medication changes during pregnancy could increase the risk of viremia and transmission of HIV to the infant. The decision of whether or not to initiate or continue to prescribe DTG should be made by the provider and the patient, after taking into account the potential risk of DTG to the fetus and the benefit of DTG for maintaining viral suppression. Adapted from Doherty M, et al. AIDS 2018. Session TUSY15. Slide credit: clinicaloptions.com

Peri-conceptional DTG: Summary Concerning early signal based on 4 cases Caution warranted pending additional data Heterogeneous group of NT defects Women need to be involved in discussion of risks/benefits Limited safety data on newer ARVs Class effect of INSTIs? Please report pregnancies prospectively to the Antiretroviral Pregnancy Registry! (apregistry.com)

Outline 1. Global AIDS epidemic 2. SEARCH and Ya Tsie (BCPP) trials 3. Peri-conceptional dolutegravir and risk of neural tube defects 4. DTG + 3TC in ART-naïve patients 5. Dolutegravir monotherapy 6. Doravirine 7. DTG BID vs EFV in TB co-infection

DTG + 3TC in treatment-naive patients Can two-drug ART regimens be used to minimize cumulative drug exposure and toxicity? DTG + RPV recently approved for virally suppressed pts Previous studies of DTG + 3TC in ART-naive participants: PADDLE (pilot study): 90% (18/20) had VL <50 c/ml at Week 48 1 ACTG A5353 (single-arm, phase II): 90% (108/120) had VL <50 c/ml at Week 24 2 1 pt with treatment-emergent resistance R263R/K and M184V 1. Cahn et al. J Int AIDS Soc. 2017;20(1):21678. 2. Taiwo et al. Clin Infect Dis. 2018;66(11):1689 1697.

GEMINI-1 and 2: DTG + 3TC vs DTG + TDF/FTC in treatment-naive patients Parallel, randomized, double blind phase III noninferiority studies Stratified by HIV 1 RNA ( vs > 100,000 copies/ml), CD4+ cell count ( vs > 200 cells/mm³) Primary Analysis Wk 48 Wk 144 N = 1433 ART naïve adults HIV 1 RNA 1,000 500,000 copies/ml, 10 days on previous ART, no major resistance assoc. mutation, no HBV; no HCV requiring rx DTG + 3TC PO QD (n = 716) DTG + TDF/FTC PO QD (n = 717) Continuation of DTG + 3TC permitted Primary endpoint: HIV 1 RNA < 50 copies/ml at Week 48 by FDA Snapshot analysis Baseline characteristics DTG + 3TC DTG + TDF/FTC Age, yrs, median (range) 32.0 (18-72) 33.0 (18-70) Female, n (%) 113 (16) 98 (14) Black/African heritage, n (%) 99 (14) 76 (11) Hispanic/Latino, n (%) 215 (30) 232 (32) HIV-1 RNA, >100,000 c/ml, n (%) 140 (20) 153 (21) CD4+ cell count, median 427 438 Slide credit: clinicaloptions.com Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. ClinicalTrials.gov. NCT02831673. ClinicalTrials.gov. NCT02831764.

GEMINI-1 and 2: DTG + 3TC non-inferior at week 48 Virologic Outcomes by FDA Snapshot Analysis Adjusted Treatment Difference, % (95% CI) HIV 1 RNA < 50 copies/ml (%) 100 80 60 40 20 0 91 93 93 94 Virologic Success ITT E PP* 3 2 2 1 Virologic Nonresponse DTG + 3TC (n = 716) DTG + TDF/FTC (n = 717) DTG + 3TC (n = 694) DTG + TDF/FTC (n = 693) 6 5 5 4 No Virologic Data ITT E DTG + TDF/FTC 4.4 1.1 DTG + 3TC *ITT E population excluding significant protocol violations. Adjusted for HIV 1 RNA ( vs > 100,000 copies/ml), CD4+ cell count ( vs > 200 cells/mm 3 ), and study (GEMINI 1 vs GEMINI 2). PP* 1.7 1.3 3.9 1.2 10 8 6 4 2 0 2 4 6 8 10 Percentage Difference Cahn P, et al. AIDS 2018. Abstract TUAB0106LB. Slide credit: clinicaloptions.com Cahn P, et al. AIDS 2018. Abstract TUAB0106LB.

GEMINI-1 and 2: Virologic response at wk 48 by baseline HIV-1 RNA and CD4+ cell count Virologic Outcomes by FDA Snapshot Analysis Patients With HIV 1 RNA < 50 c/ml (%) 100 80 60 40 20 n/n = 0 DTG + 3TC DTG + TDF/FTC 91 94 92 90 93 93 526/ 531/ 129/ 138/ 576 564 140 153 100,000 > 100,000 Baseline HIV 1 RNA, c/ml 605/ 653 79 93 618/ 50/ 662 63 > 200 200 51/ 55 Baseline CD4+ Cell Count, cells/mm 3 Reasons for virologic non response among participants with CD4 <200: DTG + 3TC (n=13): 1 confirmed virologic failure 3 with VL >50 (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 (n=4): 1 VL >50 (re suppressed) 1 investigator discretion 1 withdrew consent 1 lost to follow up Slide credit: clinicaloptions.com Cahn P, et al. AIDS 2018. Abstract TUAB0106LB.

GEMINI-1/2: Safety and resistance at wk 48 Safety Event, n (%) DTG + 3TC (n = 716) DTG + TDF/FTC (n = 717) Any AE 543 (76) 579 (81) AE in 5% of patients Headache Diarrhea Nasopharyngitis Upper RTI Nausea Insomnia Pharyngitis Back pain 71 (10) 68 (9) 55 (8) 56 (8) 27 (4) 27 (4) 36 (5) 35 (5) 75 (10) 77 (11) 78 (11) 44 (6) 53 (7) 45 (6) 32 (4) 31 (4) Drug related AE 126 (18) 169 (24) AE leading to withdrawal Neuropsychiatric 15 (2) 6 (< 1) 16 (2) 4 (< 1) Any serious AE 50 (7) 55 (8) Decline in GFR baseline to week 48 12.1% 15.5% Confirmed virologic failure (N=10) DTG + 3TC: N=6 DTG + TDF/FTC: N=4 No treatment emergent INSTI or NRTI mutations in patients with VF in either arm ACTG A5353: 1 participant with treatment emergent resistance (R263R/K, M184V) Cahn P, et al. AIDS 2018. Abstract TUAB0106LB.

GEMINI-1 and 2: Summary DTG + 3TC may be an option for initial therapy for patients who do not do RAPID (same-day) ART start Will be submitted to FDA as fixed-dose combination later this year Considerations limiting use of DTG + 3TC: Still need 3-drug ART for rapid ART start while awaiting testing No HBV co-infection, VL >500,000, or resistance Caution in patients with CD4 <200 May be best for highly adherent patients Modeling study suggested potential cost savings of $500 million over 5 years in U.S. DTG + 3TC compared to DTG/ABC/3TC 1 Girouard MP et al. Clin Infect Dis 2016:62(6):784 91.

Dolutegravir monotherapy: Don t do it! MONCAY: randomized, open label study comparing switch to DTG monotherapy vs continuing DTG/ABC/3TC in virologically suppressed chronic infection (N = 158) [1] HIV 1 RNA < 50 copies/ml at Wk 24: DTG monotherapy, 94%; triple ART, 96% VF with DTG monotherapy: Wk 24, n = 2; Wk 48, n = 7 (P =.005 vs triple ART) Emergent INSTI mutations in 2 with VF Low CD4+ cell count, detectable but not quantifiable HIV 1 RNA at screening predicted VF in multivariate analysis Slide credit: clinicaloptions.com EARLY SIMPLIFIED: DTG monotherapy noninferior to triple ART at Wk 48 in randomized, open label study of acute infection (N = 101) [2] One participant developed VFimproperly screened, found to have chronic infection Similar results in DOMONO trial DTG maintenance monotherapy: Noninferior at Wk 24, unacceptable VF afterward 8 of 95 experienced VF 3 of 8 INSTI mutations [3] 1. Hocqueloux L, et al. AIDS 2018. Abstract TUAB0103. 2. Braun DL, et al. AIDS 2018. Abstract TUAB0102. 3. Wijting I, et al. Lancet HIV. 2017;4:e547 e554.

Doravirine: a new NNRTI NNRTI with in vitro activity against common NNRTI mutations (K103N, Y181C, G190A) Daily dosing without regard to food Submitted to FDA as single agent and co-formulated as DOR/TDF/3TC - Approval anticipated in October 2018 Phase III ART-naïve trials: (data available) DRIVE-AHEAD: DOR/TDF/3TC non-inferior to EFV/TDF/FTC at 48 weeks DRIVE-FORWARD: DOR + 2 NRTIs non-inferior to DRV/r + 2 NRTIs at 48 weeks Switch studies: (awaiting data) DRIVE-SHIFT: PI/r + 2 NRTIs to DOR/TDF/3TC (Phase III) EFV/TDF/FTC to DOR/TDF/3TC (Phase II)

DRIVE-FORWARD: NRTIs + doravirine or DRV/r in treatment-naive adults Multicenter, randomized, double blind phase III study [1] Stratified by HIV 1 RNA (> vs 100,000 copies/ml) and NRTI selection (TDF/FTC or ABC/3TC) Primary Analysis Wk 48 Current Analysis Wk 96 N = 766 ART naive adults: HIV 1 RNA 1000 copies/ml within 45 days; No resistance to study drugs by genotype Doravirine 100 mg QD + 2 NRTIs* + DRV/RTV Placebo (n = 383) DRV/RTV 800/100 mg QD + 2 NRTIs* + Doravirine Placebo (n = 383) Open label extension for 96 wks *Investigator choice prior to randomization of open label TDF/FTC or ABC/3TC. Option for eligible participants to receive doravirine + 2 NRTIs in extension phase. Primary endpoint: HIV 1 RNA < 50 copies/ml at Wk 48 [2] Doravirine vs DRV/RTV: 84% vs 80% (difference: 3.9%; 95% CI: 1.6% to 9.4%) 1. Molina JM, et al. AIDS 2018. Abstract LBPEB017. 2. Molina JM, et al. The Lancet HIV 2018.

DRIVE-FORWARD: Virologic outcomes and resistance at 96 weeks HIV 1 RNA < 50 copies/ml (%) 100 80 60 40 20 n/n = 0 Treatment Difference: 7.1% (95% CI: 0.5% to 13.7%) 73.1 280/ 383 DOR + 2 NRTIs 66.0 252/ 383 DRV/RTV + 2 NRTIs Protocol-defined virologic failure (PDVF): any VL >50 c/ml after initial suppression (strict definition) Outcome DOR (n = 383) DRV/RTV (n = 383) Early d/c without PDVF, n (%) 61 (16) 71 (19) PD virologic failure, n (%) Nonresponse, n Rebound, n Successful genotype test, n DOR resistance NRTI resistance PI resistance 34 (9) 3 31 15 2 2 43 (11) 5 38 20 1 0 HIV 1 RNA < 50 copies/ml by Observed Failure Analysis, % (n) BL HIV 1 RNA, copies/ml 100,000 > 100,000 DOR 85.6 (264) 65.4 (78) DRV/ RTV 79.7 (282) 65.2 (72) Molina JM, et al. AIDS 2018. Abstract LBPEB017. Slide credit: clinicaloptions.com

Treatment-emergent resistance in doravirine trials Of 747 participants in DOR arm in treatment-naïve trials 7 (0.9%) developed DOR resistance (mainly V106 or F227) 4 retained phenotypic susceptibility to ETR 3 partially susceptible to ETR 6 failed with NRTI mutations Phenotypic susceptibility of DOR-resistant Clinical Isolates to NNRTIs Phenotypic fold change a Genotypic mutations DOR EFV ETR RPV WT 1.0 1.0 1.0 1.0 A98G/F227C/M184V >93 9.0 (R) 2.8 (S) 3.8 (R) A98G/V106I/H221Y/F227C/M184V >110 19 (R) 7.9 (PS) 10 (R) V106A/P225H/Y318F/K65R >210 4.8 (R) 0.7 (S) 1.0 (S) V106I/F227C >105 2.5 (S) 4.0 (PS) 3.4 (R) V106I/H221Y/F227C/M184V >96 1.7 (S) 1.5 (S) 1.2 (S) V106M/F227C/K65R/M184V >98 11.0 (R) 0.6 (S) 0.4 (S) Y188L/M184V >181 >120 (R) 3.4 (PS) 11 (R) a Performed by Monogram Biosciences; S: susceptible; PS: partial susceptible; R: resistant; Fold-change cut-off: EFV=3; RPV= 2; ETR=2.9-10 Lai et al. AIDS 2018. THPDB0101.

Doravirine: Summary Has not been compared to INSTI in trials No data currently in treatment-experienced populations CYP3A4-dependent metabolism May become preferred NNRTI Higher viral suppression with DOR vs DRV/r at 96 weeks Relatively few participants developed treatment-emergent resistance In patients with intolerance to INSTIs and PIs In combination with INSTI + NRTIs? DTG + ETR requires concomitant PI DTG + RPV requires full meal DTG + DOR? DTG C trough ~30% higher when co-administered with DOR 1 **no data on clinical outcomes - not yet recommended 1. Anderson MS et al. Clin Pharmacokinet 2017 Jun;56(6):661-669

DTG BID in rifampin-based TB treatment Concerns about co-administration of DTG and rifampin Rifampin reduces plasma DTG concentrations Prior PK study: 1 DTG BID with rifampin 22% higher GMR for DTG C T Compared to once daily DTG alone Limited data on HIV clinical outcomes with DTG and rifampin 1. Dooley KE et al. JAIDS 2013

INSPIRING: DTG BID + 2 NRTIs For ART-Naive Patients Receiving Rifampin-Based TB Therapy Open-label, randomized, noncomparative, active-controlled phase IIIb study Primary endpoint: Proportion of DTG-treated participants with wk 48 HIV-1 RNA < 50 c/ml (ITT-E) N = 113 ART-naive HIV-1 RNA 1000 c/ml CD4+ cell count 50 RIF-sensitive TB Randomization 3:2 DTG 50 mg BID + 2 NRTIs (n = 69) Wk 24 EFV 600 mg QD + 2 NRTIs (n = 44) DTG 50 mg QD + 2 NRTIs (n = 69) Wk 48 TB treatment 6+ months (all patients) HRZE (2 mos)* HR (4 mos) Baseline characteristics DTG (n=69) EFV (n=44) HIV-1 RNA >100,000 copies/ml, n (%) 44 (64) 24 (55) CD4+ cell count, median 208 (128, 410) 202 (92, 354) Pulmonary TB, n (%) 65 (94) 44 (100) Days from start of TB therapy to ART start 35.0 (28.0, 44.0) 33.5 (26.0, 50.5) *TB treatment containing RIF could be started up to 8 wks before randomization and no later than screening (28 to 14 days prior to randomization). DTG dose switch to occur 2 wks after TB treatment completed. Dooley KE, et al. AIDS 2018 TUAB0206 Slide credit: clinicaloptions.com

INSPIRING: Virologic outcomes DTG EFV n (%) (n=69) (n=44) Virologic success (HIV-1 RNA <50 c/ml) 52 (75) 36 (82) Virologic nonresponse 6 (9) 3 (7) VL >50 c/ml 0 2 (5) VL >50 c/ml but discontinued for other reasons 6 (9) a 1 (2) b Participants, % (95% CI) 100 80 60 40 20 0 75 82 Virologic success DTG ITT-E (n=69) EFV ITT-E (n=44) 9 7 Virologic non-response No virologic data 11 (16) 5 (11) Discontinued because of AE or death 0 2 (5) c Discontinued for other reasons 11 (16) d 3 (7) e 16 11 No virologic data 3 pts with confirmed virologic failure >400 c/ml after wk 24: 1) DTG: no NRTI or INSTI mutations 2) DTG: no NRTI mut; INSTI GT failed 3) EFV: K65R, Y181C, K103N a DTG: 3 lost to follow-up; 2 withdrawal of consent; 1 pregnancy. b EFV: 1 lost to follow-up. c EFV: 1 EFV hypersensitivity; 1 increased gamma-glutamyltransferase. d DTG: 7 lost to follow-up; 2 pregnancies; 1 physician decision; 1 withdrawal of consent. e EFV: 2 lost to follow-up; 1 withdrawal of consent (patient relocated). Dooley KE, et al. AIDS 2018 TUAB0206

INSPIRING: Viral load decay, PK data, TB outcomes, and IRIS Percentage, % 100 80 60 40 20 0-20 Modified FDA Snapshot Analysis (ITT-E) Proportion of participants with HIV-1 RNA <50 copies/ml (95% CI) 82 (95% CI: 70, 93) 75 (95% CI: 65, 86) DTG (n=69) EFV (n=44) -4 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week n (%) TB treatment success TB treatment failure (remainder not evaluated/lost to follow-up) Participants sent to adjudication committee for TB-associated IRIS Met criteria for TB-associated IRIS Pharmacokinetic data Pre-dose concentration: DTG 50 mg BID with TB treatment DTG C T (ng/ml) Time n geometric mean (%CVb) Week 8 42 870 (118) Week 24 23 964 (263) Pre-dose concentration: DTG 50 mg QD (post-tb treatment phase) DTG C T (ng/ml) Time n geometric mean (%CVb) Week 36 27 854 (208) Week 48 26 881 (281) DTG (n=69) 61 (88) 0 9 (13) 4 (6) EFV (n=44) 40 (91) 1 12 (27) 4 (9) Dooley KE, et al. AIDS 2018 TUAB0206

Changes to clinical practice after AIDS 2018 Avoid periconceptional DTG exposure until further data Involve women in conversation about this important and potent treatment option and desires for or to avoid pregnancy Consider DTG + 3TC as initial therapy in patients who are not doing RAPID ART initiation (no HBV, resistance, VL>500k, etc) Caution in patients with low CD4 or concerns about adherence Would not give DTG monotherapy Doravirine a promising NNRTI to add to our toolbox, potentially in patients with intolerance to other ARVs or in combination with INSTI + NRTIs (pending further studies) DTG can be given BID in setting of rifampin-based TB therapy Need case-by-case approach and consideration of ART history, resistance to construct optimal regimen for each patient Expert opinion

Acknowledgements Harry Lampiris, MD Matt Spinelli, MD Monica Gandhi, MD Diane Havlir, MD Clinical Care Options slides People and communities that generously participated in the studies presented

Extra slides

ARVs + rifampin ARVs may be co-administered with rifampin DTG 50 mg BID (based on INSPIRING) RAL 800 mg BID TDF EFV Do not give with rifampin BIC BIC AUC 60% lower with RIF even with BID BIC dosing 1 TAF TAF AUC 55% lower with RIF + TAF daily 2 EVG/COBI PIs What about rifabutin? Rifabutin 300 mg daily + DTG 50 mg daily 3 30% lower DTG C trough OK per DHHS guidelines but may be safer to give DTG BID + rifampin during treatment with RIF then switch to daily DTG 1. Custodio et al. CROI 2018 Abs 34 2. Cerrone et al. CROI 2018. Abs 28LB. 3. Dooley KE et al. JAIDS 2013

DHHS: alternatives to DTG in pregnancy/childbearing potential https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-andadolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential Do not give EVG/COBI DRV/COBI BIC TAF

DTG + 3TC switch studies LAMIDOL 1 Single-arm, open label study evaluating switch from suppressive 1 st line ART to DTG/3TC N = 110 patients On 3-drug ART > 4 years Wildtype at baseline Added DTG to regimen for 8 weeks, then switched from 2 NRTIs to 3TC 97% maintained viral suppression (HIV < 50 copies) at 40 weeks ASPIRE 2 Open-label, pilot randomized trial N = 90 patients Suppressed on any DHHS recommended or alternative therapy, no history of failure Randomized 1:1 to continue current 3 drug ART or switch to DTG/3TC At 48 weeks 91% suppressed in DTG/3TC arm vs 89% in cont ART arm No treatment-emergent resistance in pt who failed DTG + 3TC TANGO (NCT03446573) Phase III trial - enrolling N = 550 suppressed on TAF-based regimen (+ PI, INSTI or NNRTI) Randomized to switch to DTG + 3TC vs continue TAF-based regimen Primary completion date estimated June 2019 1. Joly et al, CROI 2017 Abstract 44LB 2. Taiwo et al, Clin Infect Dis 2018 May 17;66(11):1794-1797.

DHHS guidelines two drug regimens in treatment-experienced https://aidsinfo.nih.gov/guidelines/html/1/adult-andadolescent-arv/16/regimen-switching-in-the-setting-ofvirologic-suppression

DOR+DTG PK 1. Anderson MS et al. Clin Pharmacokinet 2017 Jun;56(6):661-669

DRIVE FORWARD: Safety at Wk 96 AE, n (%) Any AE Drug related AE in > 10% in 1 arm Diarrhea Nausea Headache Upper RTI Viral upper RTI DOR (n = 383) 324 (84.6) 123 (32.1) 65 (17.0) 45 (11.7) 57 (14.9) 51 (13.3) 44 (11.5) DRV/RTV (n = 383) 317 (82.8) 123 (32.1) 91 (23.8) 52 (13.6) 46 (12.0) 30 (7.8) 50 (13.1) Serious AE 27 (7.0) 33 (8.6) AE leading to d/c* Rash AE of clinical interest Rash Neuropsychiatric 6 (1.6) 2 (< 1) 36 (9.4) 60 (15.7) 13 (3.4) 1 (< 1) 37 (9.7) 72 (18.8) *Most occurred before Wk 48; no AE caused > 3 d/c in either arm. Molina JM, et al. AIDS 2018. Abstract LBPEB017. Grade 2 bilirubin elevation: DOR, 1.8%; DRV/RTV, 0.3% mg/dl In DOR arm, all except 1 patient had elevated predose bilirubin at BL 25 20 15 10 5 0 5 14.0 17.7 4.1 21.9 DOR 22.5 0.4 0.5 1.1 LDL C Non HDL C Total Triglycerides Cholesterol DRV/RTV 4.5 4.2 HDL C Slide credit: clinicaloptions.com

DRIVE-AHEAD: Safety Findings Squires, IAS 2017, Abstract TUAB0104LB