INTERGRASE INHIBITORS- WHAT S NEW?

INTERGRASE INHIBITORS- WHAT S NEW? Professor Margaret Johnson Royal Free London Foundation Trust October 2018

Targeting the HIV life-cycle NEW HIV VIRON MATURATION CO-RECEPTOR BINDING FUSION BUDDING CD4 BINDING ssrna Assembly HIV viron Reverse transcription of viral RNA genome Translation gp120 CD4 Chemokine Co-receptor (CCR5 or CXCR4) Proviral DNA Viral RNAs Integration Transcription CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR4, C-X-C chemokine receptor type 4; ssrna, single-strand RNA. Figure adapted from Reyskens et al. Biochim Biophys Acta 2014;1842:256 68.

Chemical Structure of INSTIs Mechanism of Action Metal-Chelating Core Halogenated Phenyl Ring Side Chain RAL EVG DTG BIC Metal-Chelating Core: Oxygen atoms chelate a pair of Mg 2+ ions and bind the integrase catalytic active site Halogenated Phenyl: Interacts with the integrase pocket that is normally occupied by the terminal 3 base of viral DNA 1. Lazerwith SE, et al. ASM 2016. Poster #414. 2. Gallant J, et al. ASM 2016. Poster #415. 3. Tsiang M, et al. ASM 2016. Poster #416. 4.Tsiang M, et al., AAC 2016;60:7086-7097. 3

Integrase inhibitors perform as well as, or better than, other classes of ARV PoC ART monotherapy: maximum change in HIV RNA (log 10 ) over 7 14 days Maximum HIV RNA reduction (Log 10 ) 900 mg BID 25 mg QD 200/100 mg or 400/100 BID 600/100 mg BID 500 mg QD 300 mg BID 300 mg BID 600 mg BID 300 mg QD 40 mg QD 10 mg single-dose 200 mg QD 600 mg BID 50 mg QD 50/100 mg QD 30 mg QD 100 mg QD 40 mg QD 1200 mg /100 mg Q12H 300 mg BID 100 mg BID 0.0-0.5-1.0-1.5-2.0-2.5-1.99-1.29-1.85-1.5-1.58-1.19-0.85-1.61-1.5-1.73-1.67-1.7-2.16-2.46-1.99-2.34-2.43-1.7-1.73-1.6-1.96-3.0 NNRTIs PIs NRTIs INSTIs MIs AI EIs *Single dose. Mean / median value as available. Day 21. Week 24. **Day 28. NB: Some of the antiviral effects were observed at doses different to the licensed dose of the ARV for treatment-naïve individuals AI = attachment inhibitor; ART = antiretroviral therapy; BID = twice daily; EI = entry inhibitor; INSTI = integrase strand transfer inhibitor; MI = maturation inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; PoC = proof of concept; QD = once daily; TAF = tenofovir alafenamide fumarate; TDF = tenofovir disoproxil fumarate. See slide notes for references.

INSTI-Containing Regimens Were Associated With Fewer Discontinuations Due to AEs Than EFV/TDF/FTC in Treatment-Naïve Patients Discontinuations for AEs (%) DTG-, EVG- and RAL-containing regimens were all associated with fewer discontinuations due to AEs than EFV/TDF/FTC over the long term Data comparing BIC with EFV or RPV are not available 20 18 16 14 12 10 8 6 4 2 0 6 EVG/c/ TDF/FTC Discontinuations from Phase 3 studies of treatment-naïve patients: INSTIs vs NNRTIs 7 EFV/ TDF/FTC Study 102 (144 weeks) 1 3 DTG/ ABC/3TC 11 EFV/ TDF/FTC SINGLE (144 weeks) 2 5 RAL + TDF/FTC 7 EFV/ TDF/FTC STARTMRK-1 (156 weeks) 3 3TC = lamivudine; ABC = abacavir; AE = adverse event; BIC = bictegravir; DTG = dolutegravir; EFV = efavirenz; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; RAL= raltegravir; RPV = rilpivirine; TDF = tenofovir disoproxil fumarate. Adapted from: 1. Wohl et al. J Acquir Immune Defic Syndr 2014;65:e118 20; 2. Walmsley et al. J Acquir Immune Defic Syndr 2015;70:515 9; 3. Rockstroh et al. Clin Infect Dis 2011;53:807 16.

Discontinuations Due to AEs Were Lower With INSTI-Based Regimens vs With Boosted PI-Based Regimens in Treatment-Naïve Patients Discontinuations for AEs (%) INSTIs have been associated with fewer discontinuations due to AEs than boosted DRV and ATV in treatment-naïve patients Data comparing BIC with any of the PIs are not available 20 18 16 14 12 10 8 6 4 2 0 3 DTG + 2NRTI 6 DRV/r + 2NRTI Discontinuations from Phase 3 studies in treatment-naïve patients: INSTIs vs PIs 4 7 DTG/ ATV/r ABC/3TC+ TDF/FTC 6 FLAMINGO ARIA Study 103 WAVES ACTG5257* (96 weeks) 1 (48 weeks) 2 (144 weeks) 3 (48 weeks) 4 (96 weeks) 5 *Rates reflect the % of patients with toxicity-associated discontinuations. 3TC = lamivudine; ABC = abacavir; AE = adverse event; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; TDF = tenofovir disoproxil fumarate. 9 EVG/c/ ATV/r + TDF/FTC TDF/FTC 2 7 EVG/c/ ATV/r + TDF/FTC TDF/FTC 1 RAL + TDF/FTC 5 14 DRV/r + ATV/r + TDF/FTC TDF/FTC Adapted from:1. Molina et al. Lancet HIV 2015; 2:e127 36; 2. Orrell et al. Lancet HIV 2017;4:e536 46; 3. Clumeck et al. J Acquir Immune Defic Syndr 2014;65:e121 4; 4. Squires et al. Lancet HIV 2016;3:e410 20; 5. Lennox et al. Ann Intern Med 2014;161:461 71.

Treatment- Experienced Treatment- Naive B/F/TAF Phase 3 Clinical Development Program * Through 48 weeks, B/F/TAF demonstrated high HIV suppression rates, non-inferior efficacy to DTG- & PI-based regimens with zero resistance development. Registrational Special Populations Study 1489 (N=600) 1,2 vs. DTG/ABC/3TC Study 1490 (N=600) 1,3 vs. DTG + FTC/TAF Study 1878 (N=520) 1,4 vs. boosted DRV/ATV + 2 NRTIs Study 1844 (N=520) 1,5 vs DTG/ABC/3TC Study 1961 (N=470) Women 6 E/C/F/(TAF/TDF) or ATV+RTV+FTC/TDF Study 1474* (N=100) Paediatrics 7 2 NRTIs + 3rd agent B/F/TAF * Study 1474 is a Phase 2/3 and has a single arm 1. Gilead Sciences. Biktarvy US Prescribing Information. February 2018. 2. Gallant J, et al. Lancet 2017;390:2063-72. 3. Sax P, et al. Lancet 2017;390:2073-82. 4. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4. 5. Molina JM, et al. CROI 2018. Boston, MA. Oral 22. 6. Kityo C, et al. CROI 2018. Boston, MA. Poster 500. 7. Gaur A, et al. CROI 2018. Boston, MA. Poster 844 7

Intergrase Cross-Resistance Profile Comparison of INSTI cross-resistance using a representative panel of HIV with integrase mutants from clinical isolates and site directed mutations Single Primary Mutations** Fold Change vs WT IN Genotype BIC DTG EVG RAL E92Q 1.2 1.6 60 18 T97A 0.7 0.9 10 1.8 F121Y* 0.4 0.6 16 5.3 Y143C* 0.9 0.9 2.2 4.3 Y143R 1.4 1.4 2.2 16 Q148H* 0.7 0.8 8.7 4.3 Q148K* 0.8 0.7 108 43 Q148R* 0.7 0.7 117 40 N155H* 1.4 1.5 41 17 R263K* 1.7 1.7 4.5 1.2 More Complex Resistance Patterns Fold Change vs WT IN Genotype BIC DTG EVG RAL T97A, N155H 1.0 1.5 95 53 E138K, Q148R 1.7 2.2 >150 54 G140A, Q148R 2.0 2.2 >150 88 G140S, Q148H 2.5 5.6 >150 >143 G140S, Q148H, G163K 2.5 5.7 >150 >143 L74M, G140C, Q148R 8.4 9.1 >150 >143 T97A, G140S, Q148H 4.4 15 >150 >143 E138K, G140S, Q148H 2.5 5.3 >150 >143 E138A, G140S, Q148H 7.2 10 >150 >143 E138K, G140A, Q148K 19 63 >150 >143 * Site directed mutants; **Single mutants from the USPI are bolded above Tsiang et al, Antimicrobial Agents and Chemotherapy, 2006 BIC or EVG < 2.5 BIC or EVG 2.5-10 BIC or EVG 10 Andreatta K et al. CROI 2018. Boston, MA. Poster #546 RAL <1.5 RAL 1.5-10 RAL >10 White K, et al. CROI 2018. Boston, MA. Poster 532 DTG <4 DTG 4-13 DTG >13 Gilead Sciences. Data on File 8

2014: Integrase inhibitors were added as preferred options for Treatment-Naive Patients in International Guidelines DHHS 1 (Dept. of Health and Human Services) NNRTI-based therapy EFV/TDF/FTC or 3TC EFV+ABC ab /3TC or FTC or RPV bc /TDF/FTC or 3TC Ritonavir-boosted PI-based therapy ATV/r or DRV/r + TDF/FTC or 3TC ATV/r + ABC a /3TC or 3TC INI-based therapy DTG + ABC a /3TC or FTC DTG + TDF/FTC or 3TC EVG/cobi/TDF/FTC d RAL + TDF/FTC or 3TC IAS-USA 2 (International Antiviral Society USA Panel) EFV e + TDF/FTC EFV e + ABC af /3TC g RPV h /TDF/FTC ATV/r ij + TDF/FTC ATV/r ij + ABC af /3TC g DRV/r j + TDF/FTC DTG k + ABC af /3TC DTG k + TDF/FTC RAL k + TDF/FTC EVG k /cobi/tdf/ftc EACS 3 (European AIDS Clinical Society) EFV l + TDF/FTC or ABC/3TC abf RPV bcm + TDF/FTC or ABC/3TC abf ATV/r n or DRV/r n + TDF/FTC or ABC/3TC abf EVG/cobi/TDF/FTC do DTG + TDF/FTC or ABC/3TC a RAL + TDF/FTC or ABC/3TC a a Only if HLA-B*5701 negative. b only if VL<100,000 c/ml. c Only if CD4>200 cells/mm 3. d Only for patients with pre-treatment CrCl>70ml/min. e Take on an empty stomach, preferably at bedtime. f ABC has been associated with increased CV risk, although conflicting data; use with caution in patients with high CV risk. g Combination of ABC/3TC less efficacious with baseline HIV-1 RNA >100,000 copies/ml than combination of TDF/FTC when given with EFV or ATV/r. h RPV should not be given with proton pump inhibitors and should be taken consistently with a full meal. i Take with food. j avoid co-administration with H2-blockers or proton pump inhibitors if possible and, if not, follow specific doses/dose separation schedules recommended in prescribing information. k Avoid simultaneous administration with antacids or other divalent cations due to chelation of INI by the cation, thereby reducing absorption. l EFV not recommended to be initiated in pregnant women or women with no reliable and consistent contraception; continuation is possible if EFV is already started before pregnancy; not active against HIV-2 and HIV-1 group O strains. m PPI contraindicated, take H2 antagonists 12 hours before or 4 hours after RPV. n Coadministration with PPI is contraindicated for treatment-experienced persons; if co-administration unavoidable, close clinical monitoring is recommended and doses of PPI comparable to omeprazole 20mg should not be exceeded and must be taken approximately 12 hours prior to ATV/r. O Not to be initiated in persons with egfr<70ml/min; not to be initiated when egrf<90ml/min unless the preferred treatment. Adapted from: 1. DHHS Guidelines November 2014; 2. Gunthard HF et al. JAMA 2014;312:410 425; 3. EACS Guidelines version 7.1 November 2014.

2015: NNRTIs were relegated to alternative for Treatment-Naive Patients in International Guidelines DHHS 1 (Dept. of Health and Human Services) NNRTI-based therapy Now alternative Ritonavir-boosted PI-based therapy DRV/r + TDF/FTC or 3TC INI-based therapy DTG + ABC a /3TC or FTC DTG + TDF/FTC or 3TC EVG/cobi/TDF/FTC d RAL + TDF/FTC or 3TC IAS-USA 2 (International Antiviral Society USA Panel) EFV e + TDF/FTC EFV e + ABC af /3TC g RPV h /TDF/FTC ATV/r ij + TDF/FTC ATV/r ij + ABC af /3TC g DRV/r j + TDF/FTC DTG k + ABC af /3TC DTG k + TDF/FTC RAL k + TDF/FTC EVG k /cobi/tdf/ftc EACS 3 (European AIDS Clinical Society) EFV l + TDF/FTC or ABC/3TC abf RPV bcm + TDF/FTC or ABC/3TC abf ATV/r n or DRV/r n + TDF/FTC or ABC/3TC abf EVG/cobi/TDF/FTC do DTG + TDF/FTC or ABC/3TC a RAL + TDF/FTC or ABC/3TC a a Only if HLA-B*5701 negative. b only if VL<100,000 c/ml. c Only if CD4>200 cells/mm 3. d Only for patients with pre-treatment CrCl>70ml/min. e Take on an empty stomach, preferably at bedtime. f ABC has been associated with increased CV risk, although conflicting data; use with caution in patients with high CV risk. g Combination of ABC/3TC less efficacious with baseline HIV-1 RNA >100,000 copies/ml than combination of TDF/FTC when given with EFV or ATV/r. h RPV should not be given with proton pump inhibitors and should be taken consistently with a full meal. i Take with food. j avoid co-administration with H2-blockers or proton pump inhibitors if possible and, if not, follow specific doses/dose separation schedules recommended in prescribing information. k Avoid simultaneous administration with antacids or other divalent cations due to chelation of INI by the cation, thereby reducing absorption. l EFV not recommended to be initiated in pregnant women or women with no reliable and consistent contraception; continuation is possible if EFV is already started before pregnancy; not active against HIV-2 and HIV-1 group O strains. m PPI contraindicated, take H2 antagonists 12 hours before or 4 hours after RPV. n Coadministration with PPI is contraindicated for treatment-experienced persons; if co-administration unavoidable, close clinical monitoring is recommended and doses of PPI comparable to omeprazole 20mg should not be exceeded and must be taken approximately 12 hours prior to ATV/r. O Not to be initiated in persons with egfr<70ml/min; not to be initiated when egrf<90ml/min unless the preferred treatment. Adapted from: 1. DHHS Guidelines April 2015; 2. Gunthard HF et al. JAMA 2014;312:410 425; 3. EACS Guidelines version 7.1 November 2014.

Key Preferred and Alternative Initial Regimens for Adults: 2018 Preferred/recommended *Regimens or components may have restrictions on use, such as HLA genotype, viral load, CD4 cell count or co-morbidities. The recommended prodrug of tenofovir (TDF or TAF) and PK booster (ritonavir [/r] or cobicistat [/c]) are listed in the table 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; /c, cobicistat boosted; DRV, darunavir DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; HLA, human leukocyte antigen; INI, integrase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; PK, pharmacokinetic; /r, ritonavir boosted; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate Recommended in certain clinical situations Regimen* IAS-USA 1 DHHS2 EACS3 DTG/ABC/3TC DTG + tenofovir/ftc TAF TDF or TAF TDF or TAF INI + BIC/tenofovir/FTC TAF NRTIs RAL + tenofovir/ftc TAF or TDF EVG/c/tenofovir/FTC TAF or TDF TDF or TAF TDF or TAF RAL + ABC/3TC EFV/tenofovir/FTC TDF TDF or TAF TDF NNRTI + EFV + ABC/3TC NRTIs RPV/tenofovir/FTC TDF or TAF TDF or TAF TDF or TAF Boosted /r or /c /r or /c Boosted ATV + PI + tenofovir/ftc TDF or TAF TDF or TAF NRTIs Boosted ATV + ABC/3TC /r or /c /r or /c Boosted DRV + /r or /c /r or /c /r or /c tenofovir/ftc TDF or TAF TDF or TAF TDF or TAF Boosted DRV + ABC/3TC /r or /c /r or /c Alternative Not listed WHO guidelines 4, 5 recommend different regimens Preferred (as stated in 2018 guidelines): DTG + 3TC + TDF 5 EFV 600 + TDF + 3TC (or FTC) 5 Alternative **: EFV 400 + TDF + [3TC or FTC] 4 Special situations **: EFV 600 a + AZT + 3TC 4 PI /r b + TDF + 3TC (or FTC) 4 Adapted from: 1. Saag MS, et al. JAMA 2018;320:379-396 2. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents, October 2017; 3. EACS Guidelines Version 9.0, October 2017; 4. Doherty M. The role of DTG based regimens in first- and second-line HIV treatment and PEP Updated WHO recommendations. Presented at 22 nd International AIDS Conference, Amsterdam, The Netherlands, July 23-27, 2018; 5. Updates Recommendations on First-Line and Second-Line Antiretroviral Regimens and Post- Exposure Prophylaxis and Recommendations on Early Infant Diagnosis of HIV, July 2018

Emerging Evidence for Use of Two-drug Regimens in Patients Switching for Reasons Other than Virologic Failure All guidelines mention switching for AEs or DDIs. Other reasons in IAS-USA, DHHS and EACS guidelines include long-term toxicity of older ARVs and dosing strategy/convenience IAS-USA 1 DHHS 2 EACS 3 WHO 2016 4 Review ARV history and resistance tests if available Older regimens may be switched to an STR TDF/FTC may be switched to TAF/FTC in order to minimize renal or bone AE Within-class switch may be possible without resistance data if genetic barrier is similar or higher Virologic Suppression: Patients may switch from 3DR to a 2DR in the setting of VS, using DTG/RPV, a boosted PI with 3TC, or DTG + 3TC can be used in patients with no prior virologic failure or transmitted drug resistance Review ARV history and resistance tests if available Within-class switch if no resistance to new ARV Between-class switch if other ARVs remain active Class-sparing strategies: DTG + RPV boosted PI + 3TC Monotherapy not recommended Alternative ARVs in the case of specific AEs also listed in Table 15 (DHHS) Review ARV history, tolerability and resistance if available If no prior VF or resistance, switch to any other preferred 1 st line regimen Replace individual ARV if new drug is active and has similar or greater genetic barrier Switch from boosted PI to unboosted ATV, NNRTI or INI only if backbone NRTIs fully active Class-sparing strategies: DTG + RPV boosted [DRV or ATV] + 3TC DRV/r monotherapy only if dual therapy not possible WHO does not recommend routine resistance testing An overall sequence of regimens is provided irrespective of reason to switch (see VF) Alternative ARVs in the case of specific AEs also listed IAS-USA, DHHS and EACS guidelines recommend using treatment history and resistance testing to guide ARV substitutions where possible AE, adverse event; STR, single-tablet regimen; VS, virologic suppression; 3DR, three drug regimen; 2DR, two drug regimen Adapted from: 1. Saag MS, et al. JAMA 2018;320:379-396; DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents, Oct. 2017; 3. EACS Guidelines Version 9.0, Oct. 2017 4. WHO Consolidated Guidelines on the Use of ARV Drugs for Treating and Preventing HIV Infection, July 2016

SWORD-1 and -2: Phase III Study Design Identically designed, randomised, multicentre, open-label, parallel-group, non-inferiority studies Screening VL <50 c/ml on INI, NNRTI, or PI + 2 NRTIs 1:1 Early-switch phase Late-switch phase Continuation phase DTG + RPV (N=513) DTG + RPV DTG + RPV CAR (N=511) Day 1 Week 52 Week 148 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 Primary endpoint at 48 weeks: subjects with VL <50 c/ml (ITT-E snapshot) * *8% non-inferiority margin for pooled data. -10% non-inferiority margin for individual studies HBV, hepatitis B virus; ITT(-E), intent to treat (- exposed) INI, integrase inhibitor; ITT-E, intent to treat exposed; NRTI, nucleoside reverse transcriptase inhibitor VF, virologic failure; VL, viral load Adapted from Llibre JM, et al. Lancet 2018;391:839 49

HIV-1 RNA <50 c/ml, % SWORD-1 and -2: Virologic Suppression* at Week 48 and Week 100 100 80 60 40 20 0 Durable efficacy maintained through 100 weeks in early switch group 95 89 Virologic success 93 n (%) <1 DTG + RPV, D1 W48, early switch (n=513) DTG + RPV, D1 W100, early switch (n=513) DTG + RPV, W52 W100, late switch (n=477) 9 3 5 5 2 Virologic non-response *FDA Snapshot; Lost to follow-up, n=3; protocol deviation, n=5 (prohibited medication use, n=3 pregnancy, n=2); withdrawal of consent, n=18 (subject relocated, n=5; travel burden, n=2; other n=9); and investigator discretion, n=2 D, day; FDA, US Food and Drug Administration; W, Week Early-switch group DTG + RPV Week 48 1 DTG + RPV Week 100 2 No virologic data Late-switch group DTG + RPV Week 100 2 Virologic success 486 (95) 456 (89) 444 (93) Virologic non-response 3 (<1) 13 (3) 10 (2) Data in window, not <50 c/ml 0 5 (<1) 3 (<1) Discontinued for lack of efficacy 2 (<1) 7 (1) 3 (<1) Discontinued while not <50 c/ml 1 (<1) 1 (<1) 0 Change in ART 0 0 4 (<1) No virologic data 24 (5) 44 (9) 23 (5) Discontinued because of AE or death 17 (3) 27 (5) 11 (2) Discontinued for other reasons 7 (1) 17 (3) 9 (2) Missing data during window but on study 0 0 3 (<1) Adapted from 1. Llibre J, et al. Lancet 2018;391:839 49 2. Aboud M, et al. IAS 2018. Poster THPEB047

Emerging Evidence for Use of Two-drug Regimens in Treatment-naïve Patients IAS-USA 1 DHHS 2 EACS 3 2-drug regimens for treatment-naïve patients* Recommended only if patient cannot take ABC, TAF or TDF: DRV/r or /c + [3TC or FTC] DRV/r or /c + [RAL or DTG]; may be less effective if CD4 <200 cells/mm 3 or HIV-1 RNA >100,000 c/ml Regimens to consider when ABC, TAF, and TDF cannot be used: LPV/r + 3TC DRV/r + RAL; only if CD4 count >200 cells/mm 3 and HIV-1 RNA <100,000 c/ml Alternative regimens include: DRV/r or /c + RAL; only if CD4 count >200 cells/mm 3 and HIV-1 RNA <100,000 c/ml Patients taking PrEP (TDF/FTC) with suspected HIV infection should add DRV/r or /c and/or DTG to TDF/FTC pending HIV-1 RNA level and resistance testing results PEP is recommended as soon as possible, before HIV-1 RNA level and resistance testing results. RAL or DTG] + TDF/FTC is recommended Immediate treatment required, before HIV-1 RNA and/or resistance test results available* Recommended regimens: DRV/r or /c + [TDF or TAF]/FTC DTG + [TDF or TAF]/FTC Resistance to DRV and DTG emerges slowly; transmitted resistance to DRV is rare and transmitted resistance to DTG has not been reported to date In chronic HIV infection: Include a drug with a high genetic barrier to resistance in the 1 st -line regimen, such as boosted PI or DTG In primary HIV infection: Preference should be given to starting a boosted PI to increase the resistance barrier An INI should also be included to induce rapid viral load suppression Consider DRV/r or /c or INI + [TDF or TAF] + FTC *Neither situation is covered by the WHO guidelines 4 LPV, lopinavir PEP, post-exposure prophylaxis PrEP, pre-exposure prophylaxis Adapted from: 1. Günthard HF, et al. JAMA 2016;316:191 210; 2. DHHS Guidelines for the Use of Antiretroviral Agents in HIV-1-infected Adults and Adolescents, October 2017; 3. EACS Guidelines Version 9.0, October 2017 4. WHO Consolidated Guidelines on the Use of ARV Drugs for Treating and Preventing HIV Infection, July 2016

HIV-1 RNA <50 c/ml, % Results: Snapshot Outcomes at Week 48 for GEMINI-1 and -2 Virologic outcome Adjusted treatment difference (95% CI) a GEMINI-1 DTG + 3TC (N=356) DTG + TDF/FTC (N=358) GEMINI-2 DTG + 3TC (N=360) DTG + TDF/FTC (N=359) DTG DTG + TDF/FTC + TDF/FTC DTG + 3TC 100 94 93 93 90 GEMINI-1-2.6 80-6.7 1.5 60 GEMINI-2-0.7 40-4.3 2.9 20 0 Virologic success 4 2 2 6 6 5 2 4 Virologic nonresponse No virologic data -10-8 -6-4 -2 0 2 4 6 8 10 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) and CD4+ cell count ( 200 cells/mm 3 vs >200 cells/mm 3 ). Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

Results: Snapshot Analysis by Visit: Pooled ITT-E Population GEMINI-1 and -2 HIV-1 RNA <50 c/ml, % 100 80 60 72 70 87 89 85 89 88 90 93 93 91 93 90 91 40 20 0 0 CD4+ cell count (cells/mm 3 ) DTG + 3TC (n=716) DTG + TDF/FTC (n=717) Adjusted mean change DTG + 3TC 224 from baseline at Week 48 a DTG + TDF/FTC 218-20 -4 0 4 8 12 16 20 24 28 32 36 40 44 48 Study visit a Calculated from a repeated measures model adjusting for study, treatment, visit (repeated factor), baseline plasma HIV -1 RNA, baseline CD4+ cell count, treatment and visit interaction, and baseline CD4+ cell count and visit interaction. Adapted from: Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB. 22nd International AIDS Conference; July 23-27, 2018; Amsterdam, the Netherlands

LATTE-2 Week 96 Results HIV-1 RNA <50 c/ml by Snapshot (ITT-ME) Oral CAB induction period (ITT-ME population) Maintenance period BL, baseline; CAB, cabotegravir; IM, intramuscular; ITT-ME, intent-to-treat maintenance exposed; Q4W, every 4 weeks; Q8W, every 8 weeks. Adapted from: Margolis et al. Lancet. 2017 Sep 23;390(10101):1499-1510

The future of Integrase Inhibitors New molecules New formulations including injectables New 2-drug regimens Safety in pregnancy Real world long term data

Intergrases and pregnancy The Tsepamo Study started in August 2014 Birth Outcomes Surveillance Funding: NIH/NICHD (R01, R Shapiro PI) Primary aims:: (1) Evaluate adverse birth outcomes by HIV-status and ART regimen (2) Determine if there is an increased risk of neural tube defects (NTDs) among infants exposed to efavirenz (EFV) from conception

NTD Prevalence Difference by Exposure

SWORD-1 and -2: Safety Profile at Week 48 and Week 100 Safety profile of late switch group was similar to early-switch group (48 weeks post-switch) Early-switch group DTG + RPV Week 48 1 (n=513) DTG + RPV Week 100 2 (n=513) Late-switch group DTG + RPV Week 100 2 (n=477) n (%) Any AE 395 (77) 453 (88) 386 (81) Any AE occurring in 10% of subjects in any group Viral upper RTI * 77 (15) 49 (10) Headache 41 (8) 59 (12) 29 (6) Upper RTI * 24 (5) 51 (10) 35 (7) Nasopharyngitis * 49 (10) 8 (2) 8 (2) Drug-related AEs 97 (19) 103 (20) 56 (12) Drug-related AEs occurring in 2% of subjects in any group Headache 11 (2) 11 (2) 8 (2) Nausea 7 (1) 8 (2) 5 (1) Serious AEs 27 (5) 58 (11) 30 (6) Fatal AEs 1 (<1) 1 (<1) 0 AEs leading to discontinuation 17 (3) 34 (7) 15 (3) Psychiatric disorders 7 (1) 12 (2) 5 (1) *Preferred term coding based on MedDRA version 20.1 rather than 19.1 (used in the Week 48 analysis), cold and common cold changed in preferred term from nasopharyngitis to viral upper RTI ; No grade 2 4 drug-related AEs of 2% frequency in any group; Subject may have had >1 AE that led to discontinuation; Grouped term includes multiple AEs. Psychiatric AEs that led to discontinuation in the early-switch group were anxiety (n=4), suicidal ideation (n=4), insomnia (n=2), depression (n=2), affective disorder, depressed mood, nightmare, and completed suicide (n=1 each); those in the late-switch group were insomnia (n=3), depression (n=2), abulia, confusional state, loss of libido, major depression, and suicidal ideation (n=1 each) RTI, respiratory tract infection Adapted from1. Llibre J, et al. Lancet 2018;391:839 49 2. Aboud M, et al. IAS 2018. Poster THPEB047