Integrase Inhibitors in second line treatment

Hongzhou Lu and Yinzhong Shen [email protected]

Shanghai Public Health Clinical Center, Fudan University WHO Collaborating Centre for Clinical Management, Training and Research on Emerging and Re-emerging Infectious Diseases 2018-06-27 Global HIV testing and care (2016)

More than 50%

In China，775,000 people living with HIV （estimated by the end of Feb 2018）

UNAIDS. Prevention gap report. 2016. UNAIDS. ENDING AIDS：Progress towards the 90–90–90 targets. 2017

Disease spectrum of hospitalized AIDS patients in Shanghai

Pulmonary infection Pulmonary TB lymphoma MAC TB meningitis

Antiretrovirals in 2018

NRTIs NNRTIs PIs INIs • (ABC) • • (ATV) • (RAL) • (ddI) • (EFV) • (DRV) • (DTG) • (FTC) • (ETR) • (FPV) • (EVG) • (3TC) • (NVP) • (IDV) • (d4T) • Nevirapine XR (NVP XR) • (LPV) • Tenofovir (TDF) • (RPV) • (NFV) • (ZDF) • (RTV) • (SQV) • (TPV)

Fusion inhibitors Entry inhibitors PK boosters Single pill regimens • (ENF) • (MVC) • Ritonavir (/r) • Atripla (EFV/TDF/FTC) • (COBI) • Eviplera (RPV/TDF/FTC) • Stribild (EVG/COBI/ TDF/FTC) • Triumeq (DTG/ABC/3TC) • Genvoya (EVG/COBI/ TAF/FTC) • Odefsky (RPV/FTC/TAF) INI, Inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PK, pharmacokinetic • Symtuza* (DRV/COBI/TAF/FTC) *EMA approval only **FDA approved only • Bictarvey** (BIC/FTC/TAF

Adapted from http://www.aidsmeds.com/list.shtml Comparing Preferred and Alternative 1st Line ARV Options (DHHS, IAS, EACS and WHO ART Guidelines)

NRTI Background NNRTI PI INSTI

TAF/TDF Guidelines +FTC ABC/3TC* AZT/3TC EFV NVP RIL ATV DRV LPV RAL EVG DTG IAS (2016)

DHHS (2018)

EACS (2017)

WHO (2016)

Preferred Alternative Not recommended/Special situations Case 1

Oct 2014 CD4 10 cells/mm3 (TDF+3TC+EFV)

Oct 2015 CD4 20 cells/mm3 HIV-RNA 830,000 c/ml Case 1

Jan 2016 HIV-RNA 446,000 c/ml

Resistance testing Drug Result Drug Result 3TC R TDF R ABC R NVP R AZT S EFV R FTC R LPV/r S Drug Result Drug Result 3TC R TDF R ABC R NVP R AZT S EFV R FTC R LPV/r S Case 2

⚫ Male, 31 years old, admitted on Oct 27, 2014 ⚫ Baseline : CD4 175 cells/ul HIV RNA: unknown ⚫ Initial regimen: TDF+EFV+3TC ⚫ 12 months after ART: CD4 43 cells/ul; HIV RNA : 28,400 c/ml

 Switch: TDF+LPV/r+3TC  Drug susceptibility: AZT+TDF+LPV/r  3 months after LPV/r : CD4 134 cells/ul HIV RNA < 40 c/ml Case 2

Jan 2014

• Lung NTM infection • Second-line regimen: Role of INSTI? • NTM-IRIS? Case 3

 AIDS and Renal aspergillosis (Renal biopsy )  ART: TDF+3TC+darunavir/ritonavir  HIV resistance

◼ How to treat aspergillosis? ◼ AMB; LAMB;VOR; ITR;CASP ◼ Switch ART to TDF+3TC+INSTI? Virologic Failure

HIV viral loads cannot be reached or maintained within defined thresholds （ After a period of time [6 months] of ART） WHO

IAS-USA China8

DHHS 1000 EACS 400 200 50

Viral Load (c/mL)

WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. 2016. Huldrych F. JAMA. 2016.316(2): 191–210; DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2016; EACS. Guideline 8.2 version. 2017; 中国疾病预防控制中心性病艾滋病预防控制中心.国家免费艾滋病抗病毒药物治疗手册(第4版). 北京:人民卫生出版社. 2016； Causes of Virologic Failure

Social issue

• Suboptimal virologic potency Regimen • Prescription errors Drug adverse effects • Malabsorption • Suboptimal pharmacokinetics Adherence-Related Factors • Drug-drug interactions

Low drug concentration

Virus replicates in the presence of drugs

Drug-resistant mutations emerge

Ayalew MB, et al. First-line antiretroviral treatment failure and associated factors in HIV patients at the University of Gondar Teaching Hospital, Gondar, Northwest Ethiopia. HIV/AIDS - Research and Palliative Care. 2016(8):141–146; Chawwana TD, et al. Factors influencing treatment failure in HIV positive adult patients on first line antiretroviral therapy. Cent Afr J Med. 2014. 60(5/8): 29-35 2017 WHO Resistance Report: Prevalence of NNRTI ADR is high among people failing ART

A systematic review of studies published between 1 January 2014 and 30 April 2017 on ADR in adults was performed. A total of 30 research cohorts from 26 studies in 30 countries were included in the analysis.

⚫ Results from this systematic review suggest that currently recommended second-line PI-based regimens remain an effective option for the majority of individuals failing first-line regimens. ⚫ The availability of affordable drugs with higher barriers to resistance (e.g. dolutegravir, or “DTG”) has the potential to address* 在蛋白酶抑制剂耐药方面，只有奈韦拉平有观察到，这是多重多态性突变所产生的结果。 concerns about emerging resistance to NNRTI-based regimens in settings where individual drug resistance testing任何利托那韦增效蛋白酶抑制剂处方预测不会出现耐药性 is not feasible. ETR，依曲韦林 ADR: Acquired drug resistance WHO. WHO HIV drug resistance report 2017 NNRthe TI had highest drug resistance rate (TDR, 10.9%; ADR, 53.3%) and PIs had the lowest drug resistance rate (TDR, 1.7%; ADR, 2.7%).

Fengdi Zhang, et al. An analysis of drug resistance among people living with HIV/AIDS in Shanghai, China. PLoS One. 2017; 12(2): e0165110. A Forecast Analysis 2015-2025 in Low- and Middle-Income Countries 14.5% of patients will be on second- or third-line regimens

30 4.2% of patients was on second- or third- 25 line regimens

20

15

10

5 Number of adults on treatment (million) treatmenton of adults Number 0 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 Third-line 0 0,1 0,1 0,2 0,3 0,4 0,5 0,5 0,6 0,6 0,6 Second-line 0,6 1 1,4 1,8 2,4 2,9 3,3 3,3 3,4 3,5 3,5 First-line 14 15,7 17,4 18,9 20,2 21,3 23,8 24 24,1 24,2 24,4

First-line Second-line Third-line

Gupta A, et al. Projected Uptake of New Antiretroviral (ARV) Medicinesin Adults in Low- and MiddleIncome Countries: A Forecast Analysis 2015-2025. Plos One. 2016(11): e0164619 WHO GUIDELINE, 2016 Guidelines for low - and middle-income countries recommend the use of 2NRTI+PI/r, regardless of whether resistance is provided

Adaptation of WHO guideline into national policies

Follow WHO guideline directly Ukraine 2NRTIs+LPV/r Alternative: ATV/r or FSV/r or SQV/r China Mexico TDF+ 3TC+ LPV/r 2NITI+LPV/r Alternative: DRV/r or other PI/r Kenya AZT+3TC+ATV/r Alternative: TDF+3TC+ Thailand ATV/r 2NRTIs+LPV/r Alternative：ATV/r or Brazil DRV/r Argentina 2NRTIs+ATV/r South Africa Alternative: DRV/r or 2NRTIs+PI/r LPV/r TDF+3TC（或FTC）+ATV/r 2NRTIs+INI AZT+3TC+ATV/r PI+ INSTI or ETV Alternative ：LPV/r or DRV/r Alternative ：MVC，ETV DTG +PI/r Are there some unmet needs?

single-pill Once-daily is not fixed-dose formulation always available is not available PI + = !

Drug-drug Adverse effects interactions*

Second-line treatment needs to be simplified and alternative treatment options should be provided in resource-limited conditions INSTIs have been approved for the treatment of HIV by the FDA and the EMA

2018 BIC 2013 DTG

O F O F H H H O O N N N N H H N N O F F O F

H O OH O OH

2012 EVG 2007 RAL

N N

O HO F O

N CI N

F HO O N N

N O O O

O OH

BIC = DTG = dolutegravir EVG = elvitegravir INSTI = integrase strand transfer inhibitor RAL = raltegravir INSTIS EXHIBIT POTENT ANTIVIRAL ACTIVITY AGAINST WILD-TYPE HIV-1 VIRUS IN VITRO

INSTI activity against wild-type HIV-11

8 7,1 7 6 5 4 (nM) 2,8 50 3 2,3 1,9 EC 2 1 0 DTG BIC EVG RAL

• The ability of INSTIs to inhibit wild-type HIV-1 replication was assessed in vitro1 – RAL had lower potency against wild-type HIV-1 compared with DTG, BIC and EVG

Note that data relating to BIC are based on published and presented data. BIC has not yet been approved by the regulatory authorities and the contents of the label are yet to be confirmed. White et al. EU Workshop on HIV 2016. Poster O-01. BIC = bictegravir; DTG = dolutegravir; EC50 = concentration required to inhibit viral replication by 50%; EVG = elvitegravir; INSTI = integrase strand transfer inhibitor; RAL = raltegravir. DTG and BIC Have Improved Activity Against INSTI-Resistant HIV-1 Mutants Compared With RAL and EVG

• The antiviral activity of INSTIs was assessed against a panel of known INSTI-resistant mutants1 – DTG and BIC displayed increased activity against INSTI-resistant mutants vs RAL and EVG1 • Note: the FC cut-offs shown below are arbitrary and are based on in vitro data only

Activity of integrase inhibitors against INSTI-resistant HIV-1 mutants1

Mean FC, IC50 Mutant DTG BIC RAL EVG E92Q 1.8 2.0 38 85 Y143R 1.9 1.8 418 14.4 Q148R 1.0 1.0 427 363 N155H 2.4 1.6 188 112 R263K 2.5 2.9 10.4 10.5 E138K/Q148K 13.7 13.7 1533 3581 G140S/Q148R 6.5 3.1 2461 868 E92Q/N155H 2.8 2.0 624 768 N155H/Q148R 4.7 7.1 2181 2169 >100 to ≤ >10 to ≤ 50 >50 to ≤ 100 >500 0 to ≤2 >2 to ≤10 500

BIC = bictegravir; DTG = dolutegravir; EVG = elvitegravir; FC = fold change; IC50 = half maximal inhibitory concentration; INSTI = integrase strand transfer inhibitor; RAL = raltegravir. 1. Tsiang et al. Antimicrob Agents Chemother 2016;60:7086–97. SELECTION OF RESISTANCE-ASSOCIATED MUTATIONS IN VITRO INDICATE BIC AND DTG HAVE A HIGHER BARRIER TO RESISTANCE THAN EVG

Progress of BIC, DTG and EVG resistance selection with HIV-1 IIIb

• Dose-escalation selection was 10,000 BIC (P10 = 256-fold, 234 days) conducted in parallel DTG (P10 = 68-fold, 202 days) for BIC, DTG and EVG EVG (P10 = 1024-fold, 119 days) 1000 T661+R263K – Resistance M501/R263K

selections )

progressed at a 50 R263K

EC R263K

faster rate with EVG - 100 R263R/K compared with BIC R263R/K M501+S119R and DTG (fold +R263K – A higher fold change 10 S119R+R263K Drug concentration Drug S153S/Y+R263R/K in EC50 was reported with EVG S153S/Y+R263R/K vs with BIC and S153S/Y+R263R/K DTG 1 0 50 100 150 200 250 – BIC and DTG have a higher barrier to Duration in culture (days) resistance emergence than EVG

BIC = bictegravir; DTG = dolutegravir; EC50 = concentration required to inhibit viral replication by 50%; Tsiang et al. Antimicrob Agents Chemother 2016;60:7086–97. EVG = elvitegravir. SECOND-LINE: Noninferiority of LPV/RTV + RAL vs LPV/RTV + NRTIs

 Similar high levels of virologic • LPV/r once daily or twice daily suppression with each strategy in • Non-inferiority demonstrated [1] primary mITT analysis • No effect of baseline VL 100 • 83% vs. 81% <200 cps at wk 48 82.6 • No major safety issues 80 80.8 • RAL arm significantly larger CD4 gains: + 167 vs. + 132 P = .59 60 (NB: ZDV use in 45% of control patients) 40 • RAL arm significantly higher total

LPV/RTV + RAL cholesterol, HDL, LDL 1 RNA < 200 c/mL (%) < c/mL 200 1 RNA

- 20 LPV/RTV + 2-3 NRTIs

HIV 0 • Non-inferiority also confirmed at 0 12 24 36 48 week 96 Wk • 80% vs 76% <200 cps

1. SECOND-LINE study group Lancet 2013; 2. Amin et al. PLOS one 2015 EARNEST: Second-line LPV/RTV-Based ART After Initial NNRTI Failure

⚫ Randomized, controlled, open-label, phase III trial ⚫ Baseline demographics (medians): HIV-1 RNA 69,782 copies/mL; CD4+ 71 cells/mm3; time on ART 4 yrs Wk 12 Wk 144

LPV/RTV + 2-3 NRTIs† HIV-infected adults and (n = 426) adolescents received first-line NNRTI-based LPV/RTV + RAL ART > 12 mos, > 90% (n = 433) adherence in previous mo, treatment failure by WHO (2010) criteria* LPV/RTV + RAL LPV/RTV monotherapy (n = 418) (n = 418) (N = 1277)

*Including clinical, CD4+ cell count (HIV-1 RNA confirmed), or virologic criteria. †Selected by physician according to local standard of care.

Paton et al, NEJM 2014; 371: 234-47 EARNEST: Clinical Outcomes at Wk 96

100 86 86 PI/NRTI 74 80 73 PI/RAL 64 60 61 PI Mono 60 56 44

40 Patients,%

20

0 Good Disease HIV-1 RNA HIV-1 RNA Control < 400 copies/mL < 50 copies/mL

⚫ “Good disease control” at Wk 96 defined as pt alive, no new WHO 4 events from Wks 0-96, and CD4+ cell count > 250 cells/mm3, and HIV-1 RNA < 10,000 copies/mL or > 10,000 copies/mL without PI resistance mutations

. Paton et al, NEJM 2014; 371: 234-47

Conclusions

⚫ Several studies have explored the efficacy of a pharmacokinetically boosted PI with an INSTI. ⚫ These studies found that regimens containing a ritonavir- boosted PI (PI/r) combined with at least one active NRTI were as active as regimens containing the PI/r combined with RAL. ⚫ Although data are limited, the other INSTIs (i.e., EVG or DTG) combined with a pharmacokinetically boosted PI may also be options in this setting (DHHS AIII).

2017 DHHS guideline. Would INSTI+2NRTIs be a better choice? DAWNING Study

• The DAWNING study was conducted to evaluate the safety and efficacy of DTG + 2 NRTIs versus a current WHO-recommended regimen of LPV/RTV + 2 NRTIs in HIV-1–infected subjects failing first-line therapy of an NNRTI + 2 NRTIs 180 168

120

63 58 56 60 55 51 45 39 29 27 17 12 7 Number of subjects of Number 0

Country

Aboud M, et al. Superior efficacy of dolutegravir (DTG) plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) compared with lopinavir/ritonavir (LPV/RTV) plus 2 NRTIs in second-line treatment: interim data from the DAWNING study. IAS 2017. Abstract.. Study Design

• Key eligibility criteria: on first-line 2 NRTIs + NNRTI regimen for ≥6 months, failing virologically (HIV-1 RNA ≥400 c/mL on 2 occasions); no primary viral resistance to PIs or INSTIs • Stratification: by HIV-1 RNA (≤ or >100,000 copies/mL), number of fully active NRTIs in the investigator-selected study background regimen (2 or <2) • Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48 using the FDA snapshot algorithm (12% noninferiority margin) Open-label randomised noninferiority phase IIIb study

DTG + 2 NRTIs DTG + 2 NRTIs Open label, Continuation phase randomised 1:1 LPV/RTV + 2 NRTIs

Randomisation Week 24 Week 48 Week 52 interim primary analysis analysis

FDA, US Food and Drug Administration; INSTI, integrase Aboud et al. IAS 2017; Paris, France. Slides TAUB0105LB. strand transfer inhibitor. Snapshot Outcomes at Week 24: ITT-E and PP Populations

Virologic outcomes Treatment differences (95% CI) 100 DTG + 2 NRTIs LPV/RTV DTG 86 82 (ITT-E, n=312) 80 72 69 LPV/RTV + 2 ITT-E NRTIs (ITT-E, 7.3 13,8 20.3 60 n=312) DTG + 2 NRTIs (PP, n=282) 40 PP LPV/RTV + 2 8.1 14,5 21.0

NRTIs (PP, n=275) 1 RNA <50 c/mL, % c/mL, <50 RNA 1

20- HIV

0 -12-10-8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 Virologic success • DTG + 2 NRTIs is superior to LPV/RTV + 2 NRTIs with respect to CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol. snapshot in the ITT-E (<50 c/mL) at Week 24, P<0.001

Brown et al. ICASA 2017; Abidjan, Côte d’Ivoire. THAB1501. Snapshot Outcomes by baseline viral load and no. active NRTIs at Week 24: ITT-E

DTG + 2 NRTIs

100 LPV/RTV + 2 NRTIs 86 82 84 80 73 74 73 69 70

60 54 55

1 RNA % c/mL, <50 RNA 1 -

40 HIV

20 257/ 215/ 208/ 181/ 49/ 34/ 45/ 35/ 212/ 180/ 312 312 242 249 70 63 61 64 251 248

0 Overall ≤100,000 >100,000 2 <2 HIV-1 RNA c/mL Fully active NRTIs

ITT-E, intent-to-treat exposed. Brown et al. ICASA 2017; Abidjan, Côte d’Ivoire. THAB1501. Treatment-Emergent Mutations in Patients With Confirmed Virologic Withdrawal (CVW)

• 10 (3%) of patients in the DTG arm and 28 (9%) of patients in the LPV/r arm met the criteria for CVW in the randomized phase • The resistance analysis was performed on subjects meeting CVW criteria

DTG + 2 NRTIs LPV/RTV + 2 NRTIs Resistance analysis (n=8) (n=24) INSTI 0 0 NRTI 0 3* K70R 0 2 M184V 0 1 K219Q 0 1 K219E 0 1 PI 0 0

* Both K70R and M184V developed in one subject, K70R and K219E in another.

• No subject receiving DTG + 2 NRTIs developed INSTI or NRTI resistance- associated mutations.

Criteria for CVW: HIV-1 RNA decrease <1 log10 c/mL by Week 16, HIV-1 RNA rebound to ≥400 c/mL after prior confirmed suppression, confirmed ≥400 c/mL on or after Week 24; INSTI, integrase strand Brown et al. ICASA 2017; Abidjan, Côte d’Ivoire. THAB1501. transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Summary of Adverse Events

DTG + 2 NRTIs LPV/RTV + 2 NRTIs (n=314)a (n=310) Any adverse event, n (%) 204 (65) 231 (75) Most common AEs (≥5% in either arm) Diarrhoea 28 (9) 98 (32) Upper respiratory tract infection 37 (12) 34 (11) Nausea 11 (4) 28 (9) Headache 22 (7) 16 (5) Lower respiratory tract infection 11 (4) 14 (5) Vomiting 5 (2) 17 (5) Any neuropsych AE 19 (6) 15 (5) Drug-related AE 47 (15) 113 (36) All drug-related grade 2-4 AEs 9 (3) 40 (13) Diarrhoea 1 (<1) 22 (7) Serious AEs or deathb 17 (5) 18 (6) Drug-related serious AEs 2 (<1) 2 (<1) AEs leading to withdrawal 7 (2) 17 (5) aTwo patients received LPV/RTV instead of DTG + 2 NRTIs. bFour fatal SAEs: DTG + 2 NRTIs, n=1 (pneumonia); LPV/RTV, n=3 (pneumonia, encephalitis/IRIS, encephalitis).

Aboud et al. IAS 2017; Paris, France. Slides TAUB0105LB. Proportion of Participants With Plasma HIV-1 RNA <50 c/mL at Week 24 by Second-Line Background Regimen

• 56% (347/624) of participants received second-line NRTIs in accordance with the WHO algorithm, and their snapshot response rates within each arm were higher than those for participants who did not • Regardless of WHO-recommended NRTI use, response rates were higher with DTG- versus LPV/r-based regimens

WHO-recommended Study Difference n/N second-line NRTIs drug (95% CI)a DTG 157/181 87% 15.1 Yes LPV/r 119/166 72% (6.6 to 23.5)a DTG 77/103 75% 8.7 No LPV/r 76/115 66% (−3.4 to 20.7)a Yes 157/181 87% 12.0 DTG b No 77/103 75% (2.2 to 21.7) Yes 119/166 72% 5.6 LPV/r b No 76/115 66% (−5.4 to 16.6) 0% 20% 40% 60% 80% 100% Participants, % CI, confidence interval; DTG, dolutegravir; LPV/r, lopinavir/ritonavir; NRTI, nucleoside reverse transcriptase inhibitor; WHO, World Health Organization. aProportion on DTG – proportion on LPV/r. bProportion with WHO-recommended NRTIs – proportion without WHO- Aboud et al. CROI 2018; Boston, MA. Poster 508. recommended NRTIs. Discussion

• One limitation of these analyses is that genotyping was used to select ≥1 fully active NRTI. In resource-limited settings, is it necessary to do resistance test to guide second-line regime selection? • Outcomes from the SECOND-LINE and EARNEST studies suggest resistance testing may not be required in lieu of an appropriate algorithm for selection of second-line NRTIs EARNEST Study

SECOND-LINE Study Group. Lancet. 2013;381:2091-2099. Paton et al. Lancet HIV. 2017;4:e341-e348. Aboud et al. CROI 2018; Boston, MA. Poster 508. Conclusions

⚫ Week 24 results demonstrated that DTG + 2 NRTIs was superior to LPV/RTV + 2 NRTIs ⚫ Response rates were highest in participants receiving DTG + WHO- recommended second-line NRTIs ⚫ Within each arm, study participants had higher response rates when receiving WHO-recommended versus other second-line NRTIs, reinforcing the WHO algorithm for NRTI selection in second-line treatment ⚫ DTG + 2 NRTIs had a favourable safety profile compared to LPV/RTV + 2 NRTIs ⚫ The DAWNING study provides important information to help guide second-line treatment decisions in resource-limited settings

DTG, dolutegravir; NRTI, nucleoside reverse transcriptase Aboud et al. CROI 2018; Boston, MA. Poster 508. inhibitor; WHO, World Health Organization. Summary Table

General

Treatment-experienced patients

Available formulations Labelled indication Available comparisons DTG 10/25/50 mg • DTG/ABC/3TC vs CAR or Adults, adolescents and • DTG + 2NRTI vs DTG DTG/ABC/3TC QD children aged ≥6 years* LPV/r + 2NRTI (50/600/300 mg) • DTG + BR vs RAL + BR BIC/FTC/TAF QD BIC Not yet approved • BIC/FTC/TAF vs bPI (75/200/25 mg) EVG/c/FTC/TDF QD • EVG/c/FTC/TDF vs Adults* (150/150/200/10 mg) PI/r + TDF/FTC • EVG/c/FTC/TDF vs EVG NNRTI + TDF/FTC EVG/c/FTC/TAF QD Adults and adolescents aged • EVG + PI/r + 3rd agent vs † (150/150/200/10 mg) ≥12 years weighing ≥35 kg RAL + PI/r + 3rd agent • EVG/c/FTC/TAF vs DRV/r + BR Adults and children aged ≥4 RAL 25/100 mg weeks • RAL + BR vs PI/r + BR Adults and children weighing RAL RAL 400 mg BID • RAL + BR vs LPV/r + BR ≥25 kg • RAL + OBT vs PBO + BR Adults and children weighing RAL 600 mg (x2 QD) ≥40 kg

*Indication in Europe, indicated for children aged ≥12 years in the FDA PI. †Indication in Europe, indicated for children weighing ≥25 kg in the FDA PI. 3TC = lamivudine; ABC = abacavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir; BID = twice daily; bPI = boosted protease inhibitor; BR = background regimen; CAR = current antiretroviral regimen; DTG = dolutegravir; DRV/r = darunavir/ritonavir; EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; LPV/r = lopinavir/ritonavir; NNRTI =non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; OBT = optimised background therapy; PI/r = protease inhibitor/ritonavir; PBO = placebo; PI = prescribing information; QD = once daily; RAL = raltegravir; TAF = fumarate; TDF = fumerate. INSTI: Efficacy in Treatment-Experienced Patients

Comparisons in treatment-experienced patients

Virologically suppressed patients Virologically failing patients

Superior to RAL + BR DTG Non-inferior to continuing current ART Superior to LPV/r + 2NRTI

BIC Non-inferior to continuing bPI No data available

Superior to continuing PI/r + TDF/FTC Superior to continuing DRV/r + BR EVG Non-inferior to RAL + PI/r + 3rd agent Non-inferior to continuing NNRTI + TDF/FTC

Superior to BR alone in patients RAL Non-inferior to continuing PI/r + BR with triple-class resistance

ART = antiretroviral therapy; BIC = bictegravir; BR = background regimen; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EVG = elvitegravir; FTC = emtricitabine; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI/r = protease inhibitor/ritonavir; RAL = raltegravir; TDF = tenofovir disoproxil fumarate. INSTI :Resistance

INSTI resistance in treatment-experienced patients

Significantly less treatment-emergent INSTI resistance vs RAL in DTG SAILING (1% vs 5%)

BIC No direct comparisons with other INSTIs available

Similar treatment-emergent INSTI resistance vs RAL in Study 145 EVG (4% vs 4%)

Significantly more treatment-emergent INSTI resistance vs DTG in SAILING (5% vs 1%) RAL Similar treatment-emergent INSTI resistance vs EVG in Study 145 (4% vs 4%)

• DTG and BIC Have Improved Activity Against INSTI-Resistant HIV-1 Mutants Compared With RAL and EVG

BIC = bictegravir; DTG = dolutegravir; EVG = elvitegravir; INSTI = integrase strand transfer inhibitor; RAL = raltegravir. 2017 DHHS Guideline 2017 EACS Guideline What will be changed in the future?

Forecast data showing proportion of adults using different ARVs as part of each line of therapy

Gupta A, et al. Projected Uptake of New Antiretroviral (ARV) Medicinesin Adults in Low- and MiddleIncome Countries: A Forecast Analysis 2015-2025. Plos One. 2016(11): e0164619 Summary

• RAL, EVG and DTG are approved INSTIs for the treatment of HIV-1; BIC is a new INSTI that is currently under investigation but was recently approved for use by the FDA. • In vitro, DTG and BIC have improved activity against INSTI-resistant mutants compared with RAL and EVG, indicating a higher barrier to resistance • DTG, EVG, RAL and BIC have shown virological efficacy in Phase 3 clinical trials of treatment-experienced patients • Resistance in clinical trials of INSTIs was rare – No treatment-emergent DTG or BIC resistance has been identified in treatment- naïve studies to date – In treatment-experienced patients, significantly less treatment-emergent resistance was reported for DTG vs RAL • INSTIs were generally well tolerated in clinical trials of both treatment-naïve and treatment-experienced patients – In head-to-head studies of INSTIs, tolerability profiles were generally comparable • The DAWNING study provides important information to help guide second-line treatment decisions in resource-limited settings

• BIC = bictegravir; DTG = dolutegravir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; RAL = raltegravir; TAF = tenofovir alafenamide fumarate.