1. Thinking of Now and Tomorrow: Emerging Treatment Paradigms
Pedro Cahn

2. Disclosures Advisory boards: Merck, ViiV Healthcare
Research funds: Abbvie, Merck, Richmond, ViiV Healthcare
Speaker at educational activities: Abbvie, Gilead, Merck, ViiV Healthcare

3. Year of FDA approval for ARV drugs used for the treatment of HIV
FDA ARV Approvals 1987–2018
BIC IBA DOR
ETR
DTG
TAF
RAL MVC
EVG
ENF
ATV
FTC
FPV
RPV
DRV
TPV
NFV
DLV
APV
TDF
Number ARVs
LPV/r
RTV
IDV
NVP
EFV
ABC
3TC
SQV
ddC
d4T
ddI
AZT
2018
Year of FDA approval for ARV drugs used for the treatment of HIV
ARV, antiretroviral; FDA, US Food and Drug Administration; HIV, human immunodeficiency virus

4. HAART Paradigms 1996 2019 CD4-guided ARV initiation
Six drugs available
HAART = three drugs
Only ARVs
One dose for all patients
Taken exclusively via the oral route
Daily dosage
Targets: RT, proteases
Treat all, regardless of CD4 counts
32 antivirals, multiple combinations
Two 2DRs approved
Antivirals and bnAbs (under investigation)
Alternative dosing
Oral and injectables (Subcutaneous dosing, Intramuscular dosing [under investigation])
Weekly, monthly, every other month dosing (under investigation)
Targets: RT, proteases, integrases, viral attachment, viral maturation, viral genes, capsid
2DR, two-drug regimen; bnAbs, broadly neutralizing antibodies; CD4, cluster of differentiation 4; HAART, highly active antiretroviral therapy; RT, reverse transcriptase

5. What is the Role of EFV in 2019?
RAL: superior at 5 years (exploratory analysis)
DTG: superior at 48 weeks (primary endpoint)
RPV: non-inferior at 48 weeks (superior in patients with BL pVL <100,000 c/mL)
DOR: non-inferior at 48 weeks and better tolerated
Impact on the CNS:
based on the ACTG meta-analysis of four studies
risk of suicidality
dyslipidemia
increasing rates of primary resistance
ACTG, AIDS Clinical Trials Group; CNS, central nervous system; DOR, doravirine; DTG, dolutegravir; EFV, efavirenz; RAL, raltegravir; RNA, ribonucleic acid; RPV, rilpivirine

6. Prevalence of NNRTI Resistance
The pre-treatment prevalence of NNRTI resistance by sampling year
Each circle represents a study and the size of the circle is proportional to the size of the study
NNRTI, non-nucleoside reverse transcriptase inhibitor

7. Simplification Strategies
Reduce number of doses a day
Reduce number of pills
Reduce drug dosage
Reduce number of drugs
Reduce number of days on ART
Expand dosing interval
ART, antiretroviral therapy

8. 12 Available STRs* (FDA) Agents Composition INSTIs BIC/FTC/TAF
INSTI + 2 NRTI
DTG/ABC/3TC
EVG/c/FTC/TDF
EVG/c/FTC/TAF
INSTI + booster + 2 NRTI
DTG/RPV
INSTI + RPV
DTG/3TC
INSTI + 1 NRTI
NNRTIs
DOR/3TC/TDF
NNRTI + 2 NRTIs
EFV/FTC/TDF,
EFV/TDF/3TC,
(EFV 400 mg/TDF/3TC)
RPV/FTC/TDF
RPV/FTC/TAF
PIs
DRV/c/FTC/TAF
PI + booster + 2 NRTIs
*According to the FDA (USA), indications vary by country; complete regimens only /c, cobicistat; ABC, abacavir; BIC, bictegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBV, hepatitis B virus; HLA-B, human leukocyte antigen class B; INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; pVL, plasma viral load; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate

9. Dose Reduction
ENCORE1: EFV 400 mg was non-inferior to approved 600 mg dose in ART-naïve adults*2
ARV dose optimization/reduction may allow more patients to be treated for the same cost1
EFV was non-inferior at a lower dose vs originally approved higher dose1
Data on EFV 400 mg during 3rd trimester of pregnancy and anti-TB treatment co-administration are based on 2 small studies3,4
N = 302
N = 285
*Modified intention-to-treat analysis
TB, tuberculosis; TLE400, fixed dose combination of efavirenz, lamivudine and tenofovir disoproxil fumarate (400 mg/300 mg/300 mg)

10. Data Supporting Switch to Newer STRs Among Virologically Suppressed Patients
Established non-inferior efficacy for switch vs BL regimens
FDA approved to treat virologically suppressed patients
Key studies
Switch from
Switch to
Boosted PI + 2 NRTIs
DTG/ABC/3TC
DTG + FTC/TDF or FTC/TAF
BIC/FTC/TAF
SWORD 1 & 24
Third agent + 2 NRTIs
DTG/RPV
STRIIVING5
EMERALD6
Boosted PI + FTC/TDF
DRV/COBI/FTC/TAF
GS-1097
TDF-based regimen
EVG/COBI/FTC/TAF
GS GS-11609
RPV/FTC/TDF
EFV/FTC/TDF
RPV/FTC/TAF
DRIVE-SHIFT10
bPI, bEVG or NNRTI + 2 NRTIs
DOR/3TC/TDF
BL, baseline; COBI, cobicistat; STR, single-tablet regimen

11. 2DR: SWORD-1 and -2: Viral Replication With HIV-1 RNA <50 c/mL
The analysis used viral load assay that reports qualitative TD or TND for HIV-1 RNA <40 c/mL
Patients with TND at BL: 78% for DTG + RPV arm, 83% for continue BL ART arm
Similar rate of post-BL TD and TND categories by BL category across arms
Qualitative viremia by TD more common with BL TD vs BL TND
No difference between arms in virologic success by TND at Week 48 (FDA Snapshot)
DTG + RPV 84% vs continued BL ART 80% (adjusted difference: 3.1%; 95% CI: -2.2% to 8.3%)
Patients with TND at BL who maintained TND, %
TD, target detected; TND, target not detected
Week

12. Continuation of DTG + 3TC permitted
GEMINI-1 and -2: DTG + 3TC vs DTG + FTC/TDF in Treatment-Naïve Patients
Parallel, international, randomized, double-blind phase III non-inferiority studies
Primary endpoint: HIV-1 RNA <50 c/mL at Week 48 (FDA Snapshot) (non-inferiority margin: –10%)
DTG + 3TC vs DTG + FTC/TDF: 91% vs 93% (difference: –1.7%; 95% CI: –4.4% to 1.1%)
no treatment-emergent INSTI or NRTI mutations in patients with VF in either arm
Stratified by HIV-1 RNA (≤ vs > 100,000 c/mL), CD4+ cell count (≤ vs > 200 cells/mm³)
Primary analysis
Week 48
Week 144
ART-naïve adults with HIV-1 RNA 1,000–500,000 c/mL, ≤10 days on previous ART, no major resistance associated mutation, no HBV infection or HCV requiring therapy
(N = 1,433)
DTG + 3TC PO QD
(n = 716)
Continuation of DTG + 3TC permitted
DTG + FTC/TDF PO QD
(n = 717)
Screening within 28 days of study start; studies double-blinded until Week 96, open label until Week 148
HCV, hepatitis C virus

13. GEMINI-1 and -2: Snapshot Analysis by Visit: Pooled ITT-E Population
DTG + TDF/FTC
DTG + 3TC
–4.4
1.1
–1.7
DTG + 3TC is non-inferior to DTG + TDF/FTC with respect to proportion achieving HIV-1 RNA <50 c/mL at Week 48 (Snapshot, ITT-E population) in both studies
–1.3
–3.9
1.2
ITT-E
Per protocol
Adjusted treatment difference (95% CI) at Week 48†
DTG + 3TC (N = 716)
DTG + TDF/FTC (N = 717)
*Calculated from a repeated-measures model adjusting for study, treatment, visit (repeated factor), BL plasma HIV-1 RNA, BL CD4+ cell count, treatment and visit interaction, and BL CD4+ cell count and visit interaction.
†Based on Cochran-Mantel-Haenszel stratified analysis adjusting for the following BL stratification factors: plasma HIV-1 RNA (≤100,000 vs >100,000 c/mL) and CD4+ cell count (≤200 vs >200 cells/mm3).
ITT-E, intention-to-treat exposed

14. BIC/FTC/TAF QD + DTG + FTC/TAF placebo QD
GS-1490: BIC/FTC/TAF vs DTG + FTC/TAF in Treatment-Naïve Adults at Week 96
Multicenter, randomized, double-blind, active-controlled non-inferiority phase III trial1
Primary endpoint: HIV-1 RNA <50 c/mL at Week 48 (non-inferiority margin: –12%)2
BIC/FTC/TAF vs DTG + FTC/TAF: 89% vs 93.0% (difference: –3.5%; 95% CI: –7.9% to 1.0%; p=0.12)
no treatment-emergent resistance in either treatment arm
Stratified by HIV-1 RNA (≤100,000 or >100,000 to ≤400,000 or >400,000 c/mL), CD4+ cell count (<50 or 50–199 or ≥200 cells/mm3), geographic region (US or ex-US)
Primary analysis
Week 48
Current analysis
Week 96
Week 144
BIC/FTC/TAF QD + DTG + FTC/TAF placebo QD
(n = 320)
Treatment-naïve adults with
HIV-1 RNA ≥500 c/mL, eGFRCG ≥30 mL/min
(N = 645)
DTG + FTC/TAF QD + BIC/FTC/TAF placebo QD (n = 325)
eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault equation; US, United States

15. GS-1490: Virologic Outcomes at Week 96
BIC/FTC/TAF (n = 314)
DTG/ABC/3TC (n = 315)
No virologic data
n/N =
Patients, %
276/314
283/315
2/ 314
7/ 315
36/ 314
25/ 315
100 80 60 40 20
87.9
89.8
HIV-1 RNA
<50 c/mL
≥50 c/mL
0.6
2.2
11.5
7.9
Virologic outcome
% Treatment difference (95% CI)
Favors
BIC/FTC/TAF
DTG/ABC/3TC
-12 -5 5 12
-1.9
-6.9
3.1
Non-inferiority of BIC/FTC/TAF vs DTG/ABC/3TC confirmed in additional analyses
No treatment-emergent resistance detected in any patient through Week 96

16. Investigational ARVs Attachment inhibitors Fusion inhibitors
Maturation inhibitors
NRTIs
Capsid inhibitors
Attachment inhibitors
Monoclonal antibodies
Rev inhibitors
Fusion inhibitors
CCR5 co-receptor antagonists
NRTIs
NNRTIs
INSTIs
PIs
CCR, C-C chemokine receptor

17. Entry Inhibitors Virus-cell fusion CD4 binding Coreceptor
gp41
gp120
V3 loop
CD4
binding
Cell
membrane
Coreceptor
CCR5/CXCR4
(R5/X4)
CCR5 antagonist
Maraviroc
Enfuvirtide
Ibalizumab
Fostemsavir
gp120 binding
* = FDA approved

18. Blinded placebo + failing regimen
BRIGHTE: Fostemsavir in Heavily Treatment–Experienced Adults at Week 96
BRIGHTE is an ongoing phase III randomized, placebo-controlled, double-blind trial
Randomized cohort*:
HTE participants failing current regimen with confirmed HIV-1 RNA
≥400 c/mL and:
Blinded FTR 600 mg
BID + failing regimen
Randomized 3:1
Open label FTR 600 mg BID + OBT
1 or 2 ARV classes remaining and ≥1 fully active and available agent per class
Unable to construct viable regimen from remaining agents
Blinded placebo + failing regimen
Day 1
Day 8 – primary endpoint
Day 9 –open label FTR + OBT
Week 24†
Week 48†
Week 96†
End of study‡
Non-randomized cohort*:
HTE participants, failing current regimen with confirmed HIV-1 RNA
≥400 c/mL and:
Open label FTR 600 mg BID + OBT
Non-randomized
0 ARV classes remaining and no remaining fully active approved agents§
Day 1
Week 24
Week 48
Week 96
End of
study‡
*There was no screening FTR IC50 criteria †Measured from the start of open label FTR 600 mg BID + OBT ‡The study is expected to be conducted until an additional option, rollover study or marketing approval is in place §Use of investigational agents as part of OBT was permitted FTR, fostemsavir; HTE, heavily treatment-experienced; IC50, 50% inhibitory concentrations ; OBT, optimized background therapy

19. BRIGHTE Study: Results
*At baseline 8 participants had HIV-1 RNA <400 copies/mL, 5 had HIV-1 RNA <200 copies/mL, and 1 had HIV-1 RNA <40 copies/mL. †At baseline 5 participants had HIV-1 RNA <400 copies/mL, 4 had HIV-1 RNA <200 copies/mL, and 1 had HIV-1 RNA <40 copies/mL.

20. New Drugs NNRTI, NRTTI, Capsid Inhibitors
Doravirine (phase III)1
Reduced plasma HIV-1 RNA to <50 c/mL in 84% patients at Week 48
Non-inferior to darunavir and efavirenz
Islatravir (MK-8591) (phase II)2
Potent at low concentrations (0.05 pmol/106 cells)
3 panels of 12 adults each received multiple daily doses in a phase II study (figure)
GS-CA1 (pre-clinical)3
Highly selective and potent
Plasma levels after 1 dose were maintained >10 weeks in rats
Potential for monthly or longer intervals in dosing
Patients with HIV-1 RNA <50 c/mL at Week 48
VL decline with islatravir-TP
GS-CA1 plasma concentrations following single SC dose in rats
Dose (mg)
Change in placebo-corrected VL 1
0.5 2 10 30
Proportion of patients
NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTTI, nucleoside reverse transcriptase translocation inhibitor; paEC95, protein-adjusted concentration producing 95% maximal effect; SC, subcutaneous TP, triphosphate; VL, viral load

21. GS-6207 (Phase I)
GS-6207, an analog of GS-CA1, is a novel, selective and highly potent inhibitor of HIV capsid function1,2
Potential for quarterly or less frequent dosing2
Measurable concentrations for at least 24 weeks
Plasma concentrations after one dose (≥100 mg) support dosing interval of ≥12 weeks
Well-tolerated following single SC doses of up to 450 mg in healthy subject2
Ongoing phase I study in patients with HIV-12

22. Why Investigate LA/ER? Advantages Infrequent dosing
A long apparent T½
Lower drug dose needed (nanoformulation)
Prevents poor adherence
Possibility of directly observed therapy
Tissue targeting (LN/macrophage uptake)
Use in patients with pill fatigue
Better protection of health privacy
Avoids treatment-related HIV stigma
Disadvantages
Injection site reactions
More frequent visits to the clinic
Increased HCP workload
Long tail, in case of unexpected toxicities
No chelation available, in case of urgent need
ER, extended release; HCP, healthcare provider; LA, long-acting; LN, lymph node

23. ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Non-Inferiority Achieved for Primary and Secondary Endpoints
Virologic outcomes
Virologic non-response (≥50 c/mL)
Virologic success (<50 c/mL)
No virologic data
Adjusted treatment difference (95% CI)*
Difference, %
Key secondary endpoint:
LA non-inferior to CAR (HIV-1 RNA <50 c/mL) at Week 48
-6.7
0.7
-3.0
CAR
CAB LA + RPV LA
-10% NI
margin
Primary endpoint:
LA non-inferior to CAR (HIV-1 RNA ≥50 c/mL) at Week 48
-1.2
2.5
0.6
6% NI margin
*Adjusted for sex and BL third agent class
CAR, current antiretroviral; NI, non-inferiority

24. FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E: Non-Inferiority Achieved for Primary and Secondary Endpoints
Virologic outcomes
Virologic non-response (≥50 c/mL)
Virologic success (<50 c/mL)
No virologic data
-3.7
4.5
0.4
-2.8
2.1
-0.4
Adjusted treatment difference (95% CI)*
Primary endpoint:
LA non-inferior to DTG/ABC/3TC (≥50 c/mL) at Week 48
6% NI margin
DTG/ABC/3TC
CAB LA + RPV LA
Difference, %
−10% NI
margin
Key secondary endpoint:
LA non-inferior to DTG/ABC/3TC (<50 c/mL) at Week 48
*Adjusted for sex and BL HIV-1 RNA (< vs ≥100,000 c/mL)
3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine

25. Long-Acting ARV Implants
Potential advantages over injectable therapy
Removable
More consistent and predictable drug release
PK not dependent on injection site
May remain in place for years (inert, non-degradable SC versions)
Potential disadvantages over injectables
Specialized device required for insertion
Minor surgical procedure to remove
Regulated as both a drug and a device
Potential difficulties moving to a generic marketplace
PK, pharmacokinetic

26. Islatravir: NRTI and Translocation Inhibitor
Islatravir-TP concentration time profile with QD dosing
Islatravir administered at low doses exhibits substantially higher inhibitors quotients than marketed NRTIs 10
0.25 mg Islatravir
0.75 mg Islatravir
5 mg Islatravir
[Islatravir-TP]PBMC
(pmol/106 cells)
100 10 1
Ctrough inhibitory quotient
TDF 300 mg QD
TAF 25 mg QD
FTC 200 mg QD
3TC 150 mg BID/ 300 mg QD
Islatravir 0.75 mg QD
Islatravir 0.25 mg QD
Islatravir 10 mg QW
n=9
n=6
n=68
n=64
n=160
n=63 1
0.1 10 20 30 40
Time, days
Islatravir-TP concentration time profile with QW dosing
Week 1
Week 3
100
100
[Islatravir -TP]PBMC
(pmol/106 cells) 10 10 1 1
0.1
0.1
QW, weekly 2 4 6 2 4 6 8 10 12 14
Time, days
Time, days
10 mg QW
30 mg QW
100 mg QW

27. Broadly Neutralizing Monoclonal Antibodies
50% of individuals infected with HIV-1 produce antibodies capable of neutralizing circulating diverse viral strains1
1% of individual produce antibodies capable of neutralizing more than 80% of circulating diverse viral strains, these individuals are called elite neutralizers2
bnMAbs3
bnMAb, broadly neutralizing monoclonal antibodies

28. Early Treatment With bnMAbs Interferes With Viral Seeding
Hyperacute infection (0–14 days)
DNA, deoxyribonucleic acid; NmAb, neutralizing monoclonal antibody; PBMC, peripheral blood mononuclear cell; SIV, simian immunodeficiency virus

29. A Timeline into the Future
HIV-1 discovered
AZT monotherapy
AZT/3TC
3DRs
STRs
The integrase era
Long acting
?????
1983
19871
19972
1996
2006
2012–13
2017
2DR
bnMAbs

30. The future looks really exciting!
Conclusions
The effectiveness of ART is already very high
The guidelines lean towards INSTIs
Other classes have new combinations (TAF/FTC/DRV/c and TDF/3TC/DOR)
Patients request simpler treatments
There are different strategies in development
2DRs (already approved by FDA and EMA)
Long-acting drugs
Experimental:
weekly oral doses
monthly injectables
implants
b-nMabs
The future looks really exciting!

31. Thank you for your attention!

32. Thank you.