Ключевые слайды по индивидуальному выбору АРТ / Key Slides on Individualized Choices in Antiretroviral Therapy.2021

Key Slides on Individualized Choices in
Antiretroviral Therapy
This program is supported by an educational grant from Gilead Sciences, Inc.

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Program Director
Chloe Orkin, MBChB, FRCP, MD
Professor of HIV
Queen Mary, University of London
Consultant Physician
Lead for HIV Research
Barts Health NHS Trust
The Royal London Hospital
London, United Kingdom

Faculty
Jean-Michel Molina, MD, PhD
Head of the Department of
Infectious Diseases
Saint-Louis Hospital, Assistance-
Publique Hôpitaux de Paris
Professor of Infectious Diseases
University of Paris
Paris, France
Cristina Mussini, MD
Head of Department of Infectious
Diseases and Tropical Medicine
Full Professor of Infectious Diseases
Infectious Diseases Clinics,
University Hospital
University of Modena and Reggio Emilia
Reggio Emilia, Italy

Faculty Disclosures
Chloe Orkin, MBChB, FRCP, MD, has disclosed that she has received
consulting fees, fees for non-CME/CE services, and funds for research
support from Gilead Sciences, GlaxoSmithKline, Janssen, MSD, and ViiV
Healthcare.
Jean-Michel Molina, MD, PhD, has disclosed that he has received funds
for research support from Gilead Sciences and consulting fees from
Bristol-Myers Squibb, Gilead Sciences, Merck, and ViiV Healthcare.
Cristina Mussini, MD, has disclosed that she has received consulting fees
from AbbVie, Angelini, Gilead Sciences, Janssen, MSD, and ViiV
Healthcare and funds for research support from Gilead Sciences, Janssen,
MSD, and ViiV Healthcare.

Outline
 Overview of Current Patient-Centered ART
 Putting Individualized Care into Practice
 Future ART: Closing the Remaining Gaps

Overview of Current Patient-Centered ART

Recommended First-line ART Regimens 2020/21
1. eacsociety.org/media/final2021eacsguidelinesv11.0_oct2021.pdf
2. clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf
3. jamanetwork.com/journals/jama/fullarticle/2771873 4. who.int/publications/i/item/9789240031593
ARV EACS1 US DHHS2 IAS-USA3 WHO4
DTG DTG + TAF/FTC or TDF/FTC
or TDF/3TC
DTG + (TAF or TDF) +
(FTC or 3TC)
DTG + TAF/FTC or
TDF/FTC or TDF/3TC
DTG + TDF + 3TC
(or FTC)
DTG DTG + ABC/3TC†
DTG/ABC/3TC† DTG/ABC/3TC† -- --
BIC BIC/TAF/FTC BIC/TAF/FTC BIC/TAF/FTC
RAL RAL + TAF/FTC or TDF/FTC
or TDF/3TC
-- -- --
DTG DTG/3TC* DTG/3TC* DTG/3TC*
DOR DOR + TAF/FTC or TDF/FTC
or TDF/3TC
DOR/TDF/3TC
-- -- --
*DTG/3TC: Avoid in patients with HBV and HIV-1 RNA >500,000 c/mL; in some guidelines, avoid in those starting ART before results of GT
resistance testing are available or with CD4+ cell count <200/μL. †If patient is HLA-B*5701 negative.

Selecting Initial ART: Factors to Consider
 Discuss ART options with patients to determine their needs and
extent to which they want to be involved in decision-making
clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf Slide credit: clinicaloptions.com
Pretreatment HIV-1 RNA
Pretreatment CD4+ cell count
HIV genotype results
HLA-B*5701 status
Individual preferences
Anticipated adherence
ART timing postdiagnosis
Initial characteristics
to consider in all
persons with HIV
Comorbid conditions
Pregnancy or wish
to become pregnant
Coinfections:
HBV, HCV, TB
Presence of specific
conditions/
factors
Regimen’s barrier to resistance
Potential AEs and drug toxicities, including
risk of development of comorbid diseases
Known/potential DDIs
Convenience
Cost and access
Regimen-specific
considerations

New Clinical Trial Data at EACS 2021
 DOR/ISL data out to 144 Weeks (abstract OS1/5)
 BIC/FTC/TAF 4-year data (abstract PE1/19)
 BIC/FTC/TAF use for rapid ART/test-and-treat (abstract PE2/7)
Molina. EACS 2021. Abstr OS1/5. Andreatta. EACS 2021. Abstr PE1/19. Bachelard. EACS 2021. Abstr PE2/7. Slide credit: clinicaloptions.com

 Parallel, international, randomized, double-blind phase III noninferiority trials in ART-naive adults with
HIV-1 RNA 1000-500,000 c/mL (N = 1433)
 Noninferiority criteria met for GEMINI-1, GEMINI-2, and pooled analysis at Wk 48, 96, and 144
 TRDF population accounted for CVW, withdrawal for lack of efficacy, withdrawal for TRAE, and participants
who met protocol-defined stopping criteria
GEMINI-1 and -2: Efficacy of DTG + 3TC
vs DTG + TDF/FTC Through Wk 144
Cahn. HIV Glasgow 2020. Poster P018. Slide credit: clinicaloptions.com
HIV-1 RNA <50 c/mL Through Wk 144 (FDA Snapshot Analysis)
HIV-1
RNA
<50
c/mL,
%
(95%
CI)
100
80
60
40
20
0
DTG + 3TC
DTG + TDF/FTC
Study Visit
144
0 4 812 16 24 36 48 60 72 84 96 108 120 132
70
84
93 93 89 90 86
84
82
84
86
72
87
93 91 87

Does DTG + 3TC Match 3-Drug ART in First-line Therapy?
1. Cahn. HIV Glasgow 2020. Abstr P018. 2. Underwood. EACS 2019. Abstr PS8/2. 3 Underwood. IAS2019. Abstr MOPEB231.
4. Cahn. Lancet. 2019;393;143. 5. Eron. HIV DART and Emerging Viruses 2018. Abstr 7. Slide credit: clinicaloptions.com
Criteria Evidence
Long-term durability? Yes, noninferior through Wk 1441
More sensitive viral markers (ie, target not detected)? No difference between 3DR and 2DR2
Frequency of blips similar with DTG + 3TC vs DTG-based 3DR? No difference in blip frequency3
Rate of and time to virologic suppression the same? No difference in time to suppression4,5
Barrier to resistance of DTG + 3TC high enough? Excellent barrier (1 case for DTG/3TC at Wk 144)4
Safety and tolerability? Better outcomes for DTG/3TC in renal and bone,
fewer drug-related AEs at Wk 964
Efficacy in high HIV-1 RNA? Yes, >100,000 HIV-1 RNA
Efficacy when CD4+ cell count <200 cells/mm3? Differences seen in FDA snapshot, as is the case in other
first-line therapy studies; no differences on TRDF analysis
(cases failed due to reasons other than virological
failure/toxicity)1

Efficacy of First-line ART at BL CD4+ Count <200 cells/μL
Adapted from: 1. Granier. CROI 2015. Abstr 550; 2. Wohl. Lancet HIV 2019;66:e355.
3. Orkin. HIV Glasgow 2018. Abstr O212. 4. Orkin. ID Week 2018. LB1. 5. Cahn. IAS 2019. Abstr WEAB0404LB. Slide credit: clinicaloptions.com
Regimen Phase III Study Name HIV-1 RNA <50 c/mL, % (n/N ) at Wk 96 (FDA Snapshot)
DTG + ABC/3TC SINGLE1 68 (39/57)
EFV/FTC/TDF SINGLE1 73 (45/62)
DTG + 2 NRTIs SPRING-21 71 (39/55)
RAL + 2 NRTIs SPRING-21 56 (28/50)
DTG/ABC/3TC GS-14892 81 (26/32)
BIC/FTC/TAF GS-14892 78 (28/36)
DRV/COBI/FTC/TAF AMBER3 73 (16/22)
DRV/COBI/FTC/TDF AMBER3 83 (24/29)
DOR/3TC/TDF DRIVE-AHEAD*4 65 (26/40)
DOR/FTC/TDF DRIVE-AHEAD*4 82 (32/39)
DTG + 3TC GEMINI-1 and -2*5 68 (43/63)
DTG + FTC/TDF GEMINI-1 and -2*5 87 (48/55)
*Studies presented ≤200 cells/mm3 (rather than <200).

Guideline Recommendation for Rapid ART
Recommendation for Rapid ART
in Patients With OIs
EACS1
Whether rapid, possibly same-day ART start is
proposed to newly diagnosed persons or postponed
until complementary assessments depends on the
setting and medical circumstances, medical indications
to start ART more urgently, and risk of loss from care
In persons with OIs, ART initiation may
have to be deferred; initiate ART as soon
as possible and within 2 wk of starting
treatment for the OI
US DHHS
Initiate ART immediately (or as soon as possible) after
HIV diagnosis to increase the uptake of ART and linkage
to care, decrease the time to viral suppression for
individual patients, and improve the rate of virologic
suppression among persons with HIV
When no effective therapy exists
for the OI, initiate ART without delay2;
Pneumocystis jirovecii: ART should be
initiated in patients, when possible, within
2 wk of Pneumocystis jirovecii diagnosis3
IAS-USA4 Start ART as soon as possible, including immediately
after diagnosis, if patient is ready
Initiation of ART is recommended
within 2 wk of initiation of
treatment for most OIs
When to Start ART
1. EACS Guidelines. v11 October 2021. 2. DHHS ART Guidelines. August 2021.
3. DHHS OI Guidelines. March 2019. 4. Saag. JAMA. 2020;324:1651. Slide credit: clinicaloptions.com

97
3
97
3
82
18
76
15
Observed (on any ART regimen)
Observed (on DTG/3TC)
ITT-E missing = failure (on any ART regimen)
FDA snapshot (on DTG/3TC)
n/N =
 Multicenter, open-label
phase III study of DTG/3TC
initiated within 14 days of
diagnosis and prior to BL labs
 DTG/3TC changed in
10 patients; all had
HIV-1 RNA <50 c/mL at Wk 48
 CVW in 2 patients, neither
with emergent resistance
‒ Both had confirmed rebound
‒ Both remained on study;
1 with HIV-1 RNA <50 c/mL and
1 with HIV-1 RNA <70/mL
 DTG/3TC well tolerated, with
few grade 2-5 drug-related AEs
(2%) and serious AEs (2%)
STAT: Wk 48 Virologic Outcomes
With DTG/3TC in Newly Diagnosed Patients
Rolle. IDWeek 2021. Abstr 75.
Patients
(%)
107/110 100/103 107/131 100/131 3/110 3/103 24/131 19/131
0
20
40
60
80
100
HIV-1 RNA <50 Copies/mL HIV-1 RNA ≥50 Copies/mL
*
*12/131 patients had no virologic data at Wk 48.

100
100
100
89
93
100
97
0
0
0
11
7
0
3
11
≥ 1,000,000…
500,000 to < 1,000,000…
≥ 500,000…
100,000 to < 500,000…
≥ 100,000…
< 100,000…
Overall…
Observed Analysis
89 11
<200
(n = 31)
≥200
(n = 79)
HIV-1 RNA <50 c/mL HIV-1 ≥50 c/mL
0% 20% 40% 60% 80% 100%
STAT: Wk 48 Virologic Suppression
With DTG/3TC by Baseline HIV-1 RNA
 High rates of virologic suppression seen in patients with BL HIV-1 RNA ≥500,000 copies/mL
‒ Median time to suppression: 60 days (95% CI: 56-169)
Rolle. IDWeek 2021. Abstr 75. Slide credit: clinicaloptions.com
90
89
89
78
82
81
82
0
0
0
9
6
0
2
10
11
11
13
12
19
16
≥ 1,000,000…
500,000 to < 1,000,000…
≥ 500,000…
100,000 to < 500,000…
≥ 100,000…
< 100,000…
Overall…
ITT-E Missing = Failure Analysis
0% 20% 40% 60% 80% 100%
HIV-1 RNA <50 c/mL HIV-1 ≥50 c/mL Data missing/patient withdrawal
Participants (%)
BL
HIV-1
RNA
(c/mL)
Participants (%)
Overall
(N = 131)
<100,000
(n = 79)
≥100,000
(n = 51)
100,000 to <500,000
(n = 32)
≥500,000
(n = 19)
500,000 to <1,000,000
(n = 9)
≥1,000,000
(n = 10)
Overall
(N = 110)
<100,000
(n = 64)
≥100,000
(n = 45)
100,000 to <500,000
(n = 28)
≥500,000
(n = 17)
500,000 to <1,000,000
(n = 8)
≥1,000,000
(n = 9)

What to Start in Pregnancy: US DHHS Guidelines Feb 2021
Two NRTIs
ABC/3TC or
TDF/FTC or TDF/3TC
TAF/FTC or AZT/3TC (alternative NRTIs)
Integrase inhibitor
Raltegravir (twice daily) or
Dolutegravir (Preferred ARV
throughout pregnancy and for
those who are trying to conceive)
or
Protease inhibitor
Darunavir/ritonavir (twice daily)
or Atazanavir/ritonavir
DHHS Perinatal Guidelines. February 2021. Slide credit: clinicaloptions.com
Plus
Bictegravir (insufficient data)
Elvitegravir/cobi (PK concerns)
DRV/cobi (PK concerns)
ATV/cobi (PK concerns)
DOR (insufficient data)
2-drug regimens not recommended

Switching ART in Patients With Virologic Suppression:
Important Addition of Treatment History
Personal communication. Prof Chloe Orkin. April 2021. Slide credit: clinicaloptions.com
Treatment history
HIV genotype results
HLA-B*5701 status
Individual preferences
Anticipated adherence
Initial characteristics
to consider in all
persons with HIV
Comorbid conditions
Pregnancy or wish
to become pregnant
Coinfections:
HBV, HCV, TB
Presence of specific
conditions/
factors
Regimen’s barrier to resistance
Potential AEs and drug toxicities, including
risk of development of comorbid diseases
Known/potential DDIs
Convenience
Cost and access
Regimen-specific
considerations

EACS: Recommended Switch Strategies
for Virologically Suppressed Persons
 Objectives of treatment modification
should be to:
‒ Eliminate or improve adverse events
‒ Facilitate adequate treatment of
comorbid conditions
‒ Improve quality of life
 Primary concern when switching
should be to sustain and not
jeopardize virologic suppression
EACS Guidelines. v11 October 2021. Slide credit: clinicaloptions.com

Switching from Suppressive ART to an STR: Noninferior
Efficacy at 48 Wks Across All Phase III Studies
Key Studies* Switch From Switch to Masking Noninferiority Shown?
380-18781 bPI + 2 NRTIs (n = 287) BIC/F/TAF (n = 290) Open-label 
380-18442 DTG/ABC/3TC (n = 281) BIC/F/TAF (n = 282) Double-blind 
380-19613 E/c/F/(TAF or TDF) or ATV/r + F/TDF (n = 236) BIC/F/TAF (n = 234) Open-label 
EMERALD4 bPI + F/TDF (n = 378) DRV/c/FTC/TAF (n = 763) Open-label 
DRIVE-SHIFT5 bPI or EVG/c or NNRTI + 2 NRTIs (n = 223) DOR/3TC/TDF (n = 447) Open-label 
TANGO6 FTC/TAF-based ART (n = 372) DTG/3TC (n = 369) Open-label 
STRIIVING7 bPI or NNRTI or INSTI + 2 NRTIs (n = 278) DTG/ABC/3TC (n = 275) Open-label 
SWORD-1/28 bPI or NNRTI or INSTI + 2 NRTIs (n = 511) DTG + RPV (n = 513) Open-label 
GS-1099 EVG/c or EFV or ATV/r + FTC/TDF (n= 447) EVG/c/FTC/TAF (n = 959) Open-label 
GS-121610 RPV/FTC/TDF (n = 314) RPV/FTC/TAF (n = 316) Double-blind 
GS-116011 EFV/FTC/TDF (n = 437) RPV/FTC/TAF (n = 438) Double-blind 
References in slide notes.
 Primary endpoint: proportion of participants with HIV-1 RNA ≥ 50 copies/mL at Wk 48

Does DTG + 3TC or DTG/RPV Work in Switch Therapy?
1. Van Wyk. J Acquir Immune Defic. 2020;85:325. 2. Cahn. Virtual HIV Glasgow 2020. Poster P018.
3. Underwood. EACS 2019. Slides PS8/2. 4. Wang. HIV Glasgow 2018. Poster P313. Slide credit: clinicaloptions.com
Criteria Evidence
Long-term durability? Yes, DTG/RPV 3 yr1, DTG/3TC 3 yr2
More sensitive viral markers (ie, target not detected)? No difference between 3DR and 2DR2
Frequency of blips similar with DTG + 3TC or
DTG/RPV vs DTG-based 3DR?
No difference in blip frequency3,4
Barrier to resistance of DTG + 3TC and DTG/RPV
high enough?
Excellent barrier; no resistance for DTG/3TC in 3 yr,
infrequent DTG/RPV1,2
Safety and tolerability?
Better outcomes for DTG/3TC and DTG/RPV renal and
bone markers vs TDF1,2

US DHHS Recommendations: February 2021 Update
DHHS Guidelines 2021. Slide credit: clinicaloptions.com
 CAB and RPV IM injections can be used as an optimization strategy for people receiving
ART with documented viral suppression for ≥3 mo (AI) who:
‒ Have no baseline resistance to either medication
‒ Have no prior virologic failures
‒ Do not have active HBV infection (unless receiving an oral HBV active regimen)
‒ Are not pregnant or planning on becoming pregnant
‒ Are not receiving medications with significant drug interactions with oral (during lead-in or
bridging therapy) or injectable CAB or RPV
 Additional key considerations
‒ Potential advantages of switching to LA ART include reducing pill fatigue, disclosure concerns, or
stigma associated with taking daily oral medications and improving QoL

Phase III FLAIR, ATLAS, and ATLAS-2M:
Efficacy of LA CAB/RPV at Wk 48
1. Orkin. NEJM. 2020;382:1124. 2. Swindells. NEJM. 2020;382:1112. 3. Overton. Lancet 2021;396:1994.
Monthly IM Maintenance Therapy Following Daily Oral ART Induction Monthly vs Every-2-Mo IM Dosing
FLAIR1
(N = 629)
ATLAS2
(N = 618)
ATLAS-2M3
(N = 1,045)
Treatment-naive adults with
HIV-1 RNA <50 copies/mL for 20 wk
receiving daily oral ARV therapy
Adults with HIV-1 RNA
<50 copies/mL for ≥6 mo
Adults with HIV-1 virologically
suppressed for ≥6 mo
or monthly dosing
Established noninferiority of long-acting therapy compared with
daily oral regimens; every-2-mo dosing noninferior to monthly dosing1-3

LA CAB + RPV as Switch Therapy for People With
HIV-1 RNA <50 copies/mL?
3DR, 3-drug regimen; VL, viral load
Criteria Evidence
Long-term durability? Yes, phase III data FLAIR out to Wk 1441
Can it be given both monthly and every 2 mo? Yes, ATLAS-2M showed noninferior efficacy2
Safety and tolerability? Well tolerated1-3
Injection site reactions?
Mostly grade 1-2, resolve within 3-7 days, very few
discontinue due to ISRs1-3
Patient satisfaction?
Study participants preferred injectable ART to oral
and 2-mo to monthly
Is OLI always needed?
No, in FLAIR outcomes were similar with no
hypersensitivity1
Resistance?
<1.5% fail virologically, but those who fail do so mostly
with resistance, usually to 2 classes
1. Orkin. NEJM. 2020;382:1124. 2. Swindells. NEJM. 2020;382:1112. 3. Overton. Lancet 2021;396:1994. Slide credit: clinicaloptions.com

Living With COVID-19: The New World
 Whom to bring in for F2F?
 How are virtual MDTs managed?
 How do we switch ART?
Expert opinion of presenter. Slide credit: clinicaloptions.com

Treatment Goals: To Enable a Full and Good Life
Rapid and durable
viral suppression
Identifying and managing
 Coinfections, STIs, and OIs
 Vaccinations
Managing comorbidities
and prescribing
 Reducing polypharmacy
 Avoiding DDIs
Preventing HIV transmission
Reducing stigma
Supporting mental health
 Assess and support mental health
 Assess chem use and alcohol,
onward referrals
Facilitating life goals
 Pregnancy
 Breastfeeding
 Trans health
 Adolescent transition
U=U
Adapted by Prof Orkin from: DHHS ART Guidelines. Living with HIV. December 2019.
clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/treatment-goals?view=full Slide credit: clinicaloptions.com

Putting Individualized Care into Practice

Patient Case 1: Background
 79-yr-old Italian male presented for care with oral thrush and shortness
of breath that started 2 wk before
‒ SARS-CoV-2 nasal swab: negative
 HIV test result: positive
 Arterial PaO2: 54 mm Hg
 BAL: diagnostic for Pneumocystis jirovecii
 Started on cotrimoxazole and dexamethasone plus fluconazole

ACTG 5164: Immediate vs Deferred ART in
Patients With Acute Opportunistic Infections
 Randomized trial of ART started within 48 hr of
randomization and within 14 days of starting
acute OI tx (immediate) vs after completion of
acute OI tx, ie, between Wk 4 and 32 (deferred)
‒ Patients with TB ineligible
 Rate of AIDS progression or death 14.2% in
immediate ART group vs 24.1% in deferred ART
group (P = .035)
 No differences in IRIS between arms:
(6% in immediate ART vs 9% deferred ART)
 Most common OIs: Pneumocystis jirovecii (63%),
cryptococcus (12%), bacterial infection (12%)
Zolopa. PLoS One. 2009;4:e5575. Slide credit: clinicaloptions.com
Wk to Death/New AIDS-Defining Illness
Time to AIDS Complication or Death
0 8 16 24 32 40 48
0
0.2
0.4
0.6
0.8
1.0
Immediate ART
Deferred ART
HR: 0.53 (99% CI: 0.35-0.92; P =.023)
n = 94
n = 116
141 129 124 119 116
141 117 108 98 94
Probability
of
Surviving
Without
Death/New
AIDS-Defining
Event

Guideline Recommendation for Rapid ART
Recommendation on Rapid ART in
Patients With OIs
EACS1
Whether rapid, possibly same-day ART start is
proposed to newly diagnosed persons or postponed
until complementary assessments depends on the
setting and medical circumstances, medical indications
to start ART more urgently and risk of loss from care
In persons with OIs, ART initiation may
have to be deferred; initiate ART as soon
as possible and within 2 wk after starting
treatment for the OI
DHHS
Initiate ART immediately (or as soon as possible) after
HIV diagnosis to increase the uptake of ART and linkage
to care, decrease the time to viral suppression for
individual patients, and improve the rate of virologic
suppression among persons with HIV
When no effective therapy exists for the
OI, initiate ART without delay2;
Pneumocystis jirovecii: ART should be
initiated in patients, when possible, within
2 wk of Pneumocystis jirovecii diagnosis3
IAS-USA4
Start ART as soon as possible, including immediately
after diagnosis, if patient is ready
Initiation of ART is recommended
within 2 wk of initiation of
treatment for most OIs
Recommendations for Rapid ART
1. EACS Guidelines. v11 October 2021. 2. DHHS ART Guidelines. August 2021.
3. DHHS OI Guidelines. March 2019. 4. Saag. JAMA. 2020;324:1651. Slide credit: clinicaloptions.com

Overall
Baseline HIV-1 RNA (copies/mL)
>100,000
≤100,000
Baseline CD4+ count (cells/µL)
>200
≤200
GEMINI-1 and -2: DTG + 3TC vs DTG + TDF/FTC in ART-
Naive Patients With Advanced Disease
Cahn. Lancet. 2019;393:143.
HIV-1 RNA <50 copies/mL at Wk 48 by BL HIV-1 RNA and
CD4+ Cell Count (Snapshot Analysis)
Difference in Proportion (%)
Two-drug regimen Three-drug regimen

Questions to Consider for Case 1
 When would you start ART in
this patient?
 Which regimen would you
choose for this patient?
‒ DTG/ABC/3TC
‒ DTG + TAF/FTC or TDF/FTC or
TDF/3TC
‒ BIC/TAF/FTC
‒ RAL + TAF/FTC or TDF/FTC or
TDF/3TC
 79-yr-old Italian male with oral thrush and
shortness of breath
‒ SARS-CoV-2 negative; HIV positive
 Arterial PaO2: 54 mm Hg
 BAL: diagnostic for Pneumocystis jirovecii
 Started on cotrimoxazole and
dexamethasone plus fluconazole

 30-yr-old female from Ghana
‒ Arrived in Italy 5 yr ago
 Started ART with RPV/FTC/TDF
‒ Virologic suppression maintained with CD4+ cell count >600 cells/mm3
‒ Describes difficulty taking medication regularly
 At today’s visit, the patient informs you that she is pregnant

 Randomized, open-label trial of DTG- vs EFV-based ART in pregnant women from Uganda and South Africa
 DTG-based therapy achieved more rapid virologic suppression vs EFV-based therapy
DolPHIN-2: DTG-Based ART vs EFV-Based ART in
HIV-Infected Mothers Initiating ART in Third Trimester
Kintu. CROI 2019. Abstr 40LB.
Time to HIV-1 RNA <50 copies/mL
(Primary Endpoint)
Time to HIV-1 RNA <1000 copies/mL
Days Since Randomization
Proportion
With
Outcome
1.0
0.8
0.6
0.4
0.2
0
0 15 30 45 60 75
HR: 2.73 (95% CI: 1.91-3.89;
log-rank P < .0001)
Days Since Randomization
Proportion
With
Outcome
1.0
0.8
0.6
0.4
0.2
0
0 15 30 45 60 75
DTG-based ART
EFV-based ART
HR: 1.49 (95% CI: 1.14-1.95;
log-rank P = .0011)

DolPHIN-2: Virologic Suppression at Delivery
Kintu. CROI 2019. Abstr 40LB.
*RR: 1.66 (95% CI: 1.32-2.08).
Results unaffected by BL HIV-1 RNA or CD4+ cell count, gestation at entry, maternal age, or country in multivariate analysis.
HIV-1 RNA < 50 Copies/mL at Delivery in Evaluable ITT Patients
Patients
With
Outcome
(%)
Overall*
(N = 237)
< 100,000
(n = 198)
≥ 100,000
(n = 39)
BL HIV-1 RNA,
copies/mL
≥ 200
(n = 206)
< 200
(n = 31)
BL CD4+ Cell Count,
cells/mm3
< 36
(n = 200)
≥ 36
(n = 37)
Gestation,
Wks
P < .0001 P < .0001
P = .063
P = .124
P < .0001 P < .0001
P = .219
100
80
60
40
20
0
73.8
42.6
78.9
48.9 44.4
14.3
75.9
45.9
57.1
23.5
74.5
44.1
70.8
30.8
DTG-based ART
EFV-based ART

 Randomized, open-label, international phase III noninferiority trial1,2
 Virologic efficacy of DTG-based ART superior to that of EFV/FTC/TDF: 98% vs 91% with viral
suppression at time of delivery (P = .0052)
 Significantly higher infant mortality rate in post-hoc analysis with EFV/FTC/TDF vs DTG-based ART
IMPAACT 2010: DTG + FTC/TAF vs DTG + FTC/TDF vs
EFV/FTC/TDF for First-line ART During Pregnancy
1. Chinula. CROI 2021. Abstr 177. 2. Lockman. Lancet. 2021;397:1276. Slide credit: clinicaloptions.com
Proportion of Women With HIV-1 RNA < 200 c/mL at Delivery Visit
DTG arms combined
EFV/FTC/TDF
Intention to Treat Per Protocol
Women
With
HIV-1
RNA
<200
copies/mL
at
Delivery
(%)
100
80
60
40
20
0
97.5% 91.0%
Risk difference: 6.5%
(2.0%-10.7%; P = .005)
Risk difference: 6.0%
(1.6%-10.3%; P = .008)
97.5%
91.4%

IMPAACT 2010: Average Weekly Maternal Weight
Gain and Association With Pregnancy Outcomes
Hoffman. CROI 2021. Abstr 176. Slide credit: clinicaloptions.com
Average Weekly Maternal Weight Gain
Average
Weekly
Weight
Gain
(kg)
0.5
0.4
0.3
0.2
0.1
0
0.378
0.319
0.291
P <.001
P = .19
P = .011
Recommended IOM weight gain
2nd/3rd trimesters (0.42 kg/wk)
DTG + FTC/TAF DTG + FTC/TDF EFV/FTC/TDF

Antiretroviral Pregnancy Registry:
Interim Report January 1989 Through January 2021
http://apregistry.com/forms/interim_report.pdf.
Summary of Birth Defect Rates Among First Trimester Exposures to January 2021
Lamivudine
TDF
Zidovudine
Emtricitabine
Ritonavir
Lopinavir
Atazanavir
Abacavir
Nelfinavir
Nevirapine
Efavirenz
Stavudine
Darunavir
Rilpivirine
Dolutegravir
Raltegravir
Cobicistat
TAF
Didanosine
Elvitegravir
Indinavir
Telbivudine
First Trimester APR
Any Trimester APR
MACDP
TBDR
81/3453
33/1447
310/10950
Defects/Live Births
169/5433
108/4483
136/4225
104/3952
30/1439
43/1368
47/1212
35/1171
28/1166
21/811
24/643
19/576
8/557
22/526
15/486
17/473
20/427
11/371
7/289
3/254
590/20686
Prevalence (%)
0 1 2 3 4 5 6 7 8 9
MACDP
TBDR
2.63
2.35
2.28
2.83
Prevalence (%)
3.11
2.41
3.22
2.08
3.14
3.88
2.99
2.40
2.59
3.73
3.30
1.44
4.18
3.09
3.59
4.68
2.96
2.42
1.18
2.85
2.72
4.17
2.71
2.15
1.87
1.57
2.53
Lower 95% CI
2.66
1.98
1.41
2.28
2.86
2.09
1.60
1.61
2.40
2.00
0.62
2.64
1.74
2.11
2.88
1.49
0.98
0.24
2.63
2.68
4.15
3.41
3.18
2.91
3.19
3.16
Upper 95% CI
3.61
2.90
3.80
2.96
4.21
5.12
4.13
3.45
3.93
5.50
5.10
2.81
6.27
5.04
5.69
7.14
5.24
4.93
3.09
2.76
4.19

 How would you approach managing
this patient’s ART?
‒ Continue the same treatment
‒ Change to DTG/ABC/3TC
‒ Change to DTG + TDF/FTC or
TDF/3TC or TAF/FTC
‒ Change to RAL + TDF/FTC or
TDF/3TC
‒ Change to DRV/r + TDF/FTC or
TDF/3TC
‒ Change to CAB/RPV
 What mode of delivery would you
recommend for this patient?
‒ C-section
‒ Vaginal delivery
‒ Forceps delivery
 30-yr-old female from Ghana
‒ Arrived in Italy 5 yr ago
 Started ART with RPV/FTC/TDF
‒ Virologic suppression maintained with
CD4+ cell count >600 cells/mm3
‒ Describes difficulty taking medication
regularly
 Now pregnant

 31-yr-old man on stable ART with DTG/ABC/3TC initiated January 2020
 Virologic suppression maintained with CD4+ cell count >700 cells/mm3
 Ongoing care provided virtually due to COVID-19
 The patients has described bad dreams, which were attributed to
pandemic anxiety
 At the last visit, the patient asks to change ART

Study 380-4030: Switching to BIC/FTC/TAF in
Patients With Virologic Suppression on DTG + FTC/TAF
 Randomized, double-blind noninferiority study (N = 567)
Sax. Clin Infect. Dis. 2021;73:e485. Slide credit: clinicaloptions.com
Virologic Outcomes at Wk 48
HIV-1 RNA
<50 c/mL
HIV-1 RNA
≥50 c/mL
No Virologic
Data
1/
284
3/
281
265/
284
256/
281
22/2
81
18/2
84
BIC/FTC/TAF
(n = 284)
DTG + FTC/TAF
(n = 281)
Patients
(%)
n/N =
100
80
40
60
20
0
< 1 1
93 91
6 8
-4 -2 0 2 4
Favors DTG + FTC/TAF
Favors BIC/FTC/TAF
-0.7
1.0
-2.8
HIV-1 RNA ≥50 copies/mL
Treatment Difference, % (95% CI)

Study 380-4030: Safety
AEs, n (%)
BIC/FTC/TAF
(n = 284)
DTG +
FTC/TAF
(n = 281)
Any AE 236 (83) 243 (86)
Grade 3/4 AE 23 (8) 13 (5)
Serious AE 30 (11) 19 (7)
Study drug-related AE 41 (14) 28 (10)
Study drug-related serious
AE
0 1 (<1)
AE leading to study drug
d/c, n (%)
6 (2) 6 (2)
Death 1 (<1) 1 (<1)
AEs ≥5% in Either
Arm, n (%)
BIC/FTC/TAF
(n = 284)
DTG + FTC/TAF
(n = 281)
Nasopharyngitis 32(11) 28 (10)
Diarrhea 23 (8) 32 (11)
Upper RTI 20 (7) 30 (11)
Headache 13 (5) 23 (8)
Arthralgia 16 (6) 17 (6)
Influenza 16 (6) 14 (5)
Fatigue 21 (7) 8 (3)
Insomnia 18 (6) 11 (4)
Back pain 15 (5) 11 (4)
Bronchitis 14 (5) 11 (4)
Pain in extremity 12 (4) 11 (4)
Cough 6 (2) 16 (6)
Sax. Clin Infect. Dis. 2021;73:e485.

DETOX: Reversibility of Sleep Disturbances in
Suppressed Patients Receiving DTG/3TC/ABC
 Multicenter, open-label, randomized trial assessing reversibility of sleep disturbances in
virologically suppressed patients on DTG/3TC/ABC (>12 wk) without reported insomnia
(N = 72)
 Primary endpoint: difference in PSQI scores between study arms at Wk 4
 Secondary endpoints: AEs, HAD
 All patients completed 8 wk on DRV/COBI/FTC/TAF
Virologically suppressed
patients on DTG/ABC/3TC
(≥4 wk); PSQI >5
(N = 72)
DTG/3TC/ABC
(n = 35)
DRV/COBI/FTC/TAF
(n = 37)
Perez-Valero. CROI 2021. Abstr 339. Slide credit: clinicaloptions.com
DRV/COBI/FTC/TAF
(n = 35)
Day 1 Wk4 Wk8 Wk12

DETOX: Baseline Characteristics
Characteristic DTG/3TC/ABC (n = 35) DRV/COBI/FTC/TAF (n = 37)
Mean age, yr (SD) 46.1 (10.5) 48.4 (11.5)
Male sex, n (%) 29.0 (82.9) 32.0 (86.5)
White race, n (%) 26.0 (74.3) 28.0 (75.7)
Toxic habits, n (%) 20.0 (57.1) 24.0 (64.9)
IDU, n (%) 6.0 (17.1) 15.0 (40.5)
Mean time since HIV diagnosis, yr (SD) 12.2 (10.3) 13.1 (10.3)
Mean time HIV undetectable, yr (SD) 5.3 (5.0) 5.56 (4.0)
Mean time on DTG/3TC/ABC, yr (SD) 3.1 (1.6) 2.7 (1.3)
Mean CD4+ nadir, cells/mm3 (SD) 358.0 (232.5) 230 (215)
Mean CD4+ cell count, cells/mm3 (SD) 727.4 (315.7) 611.1 (190.9)
Anxiety screen positive, n (%) 21.0 (60) 19.0 (51.4)
Depression screen positive, n(%) 10.0 (28.6) 7.0 (18.9)

DETOX: CNS Results at Wk 4
 No virologic failure observed during study; AEs 37.7% (all grade 1/2)
 PSQI, CNS AEs, and HAD scores significantly reduced after switch to DRV/COBI/FTC/TAF
 PSQI components: Patients reporting moderate
to severe disturbances in subjective sleep
quality and sleep latency reduced after switch
from DTG/3TC/ABC to DRV/COBI/FTC/TAF
Baseline Week 4
P <.001
PSQI Score
DTG/3TC/ABC DRV/COBI/FTC/TAF
36.5 35.3 38.2
26.7
P <.001
CNS AEs Score
27.1 25.8 27.8
14.5
P = .003
HAD Anxiety Score
39.1 36.8 38.8
23.3
P = .203
HAD Depression Score
27.8 24.1 22
15.2
P = .007
Subjective Sleep Quality
80.0
74.3
83.8
29.7
P = .045
82.9 82.9 81.1
51.4
Sleep Latency
PSQI Components

 How would you respond to the
patient’s request to change ART,
given guidance on virtual HIV
care during the pandemic?
 Which regimen would you
choose if changing this patient’s
ART?
‒ DTG + 3TC
‒ BIC/TAF/FTC
‒ DOR/TDF/3TC
‒ RPV/TAF/FTC
‒ DRV/COBI/TAF/FTC
‒ LA CAB/RPV
 31-yr-old man on stable ART with
DTG/ABC/3TC initiated January 2020
 Virologic suppression maintained with CD4+
cell count >700 cells/mm3
 Ongoing care provided virtually due to
COVID-19
 The patients has described bad dreams,
which were attributed to pandemic anxiety
 The patient asks to change ART

Future ART: Closing the Remaining Gaps

Global Antiretroviral Coverage
 37.7 million people including
36 million adults with HIV in 20201
‒ 74% of adults and 54% of children
on ART
 2030 UNAIDS target: 95% on ART
‒ How to get there?
 >10 million people with HIV on
DTG/TDF/3TC3
‒ Could we do better?
1. unaids.org/en/resources/fact-sheet.
2. clintonhealthaccess.org/2021-hiv-market-report-the-state-of-the-hiv-market-in-low-and-middle-income-countries/
3. www.clintonhealthaccess.org/hiv-mid-year-market-memo-2021/ Slide credit: clinicaloptions.com
Adults on ART and Adult ART Coverage in
Low- and Middle-Income Countries2
49%
61%
55%
64%
70%
75%
80%
70%
60%
50%
40%
30%
20%
10%
0%
30M
25M
20M
15M
10M
5M
ART
Coverage,
Adults
Adults
on
ART
LMIC total adults on ART
(Actual/projected) LMIC ART coverage for adult PWH (%)

Ideal ART Without HIV Cure on the Horizon
 Effectiveness
‒ Strong antiviral activity against all HIV-1
subtypes and HIV-2
‒ Activity against drug-resistant HIV-1
(resistant to NRTIs, PIs, NNRTIs, INSTIs)
‒ Activity against HBV
 Adherence
‒ Simple use (self-administered with high
forgiveness; LA formulations (oral or
injectable)
‒ Simple assessment of long-term adherence
(dried blood spots for TFV-DP)
 Breakthrough virologic failure
‒ Low risk for resistance and cross-resistance to
avoid compromising future options
 Safety and tolerability
‒ Almost perfect without need for safety
monitoring
‒ No weight gain, safe for pregnant women,
adolescents, and babies
‒ Limited or no DDI, eg, rifampin, food effect, PPIs
 Implementation
‒ Easy to store (room temperature, stability)
‒ Affordable cost

Approved and Investigational Long-Acting ART
 Oral
‒ Islatravir1
‒ MK-85072
 Parenteral
‒ Intramuscular: cabotegravir/rilpivirine LA1
‒ Subcutaneous: lenacapavir,1 bNabs
‒ Implants: islatravir,3 cabotegravir,4 TAF4
‒ bNabs5: IV, SC
 Topical
‒ Patches for intradermal delivery: bictegravir6
1. clinicalinfo.hiv.gov/en/drugs. 2. Ankrom. HIV Therapy Glasgow 2020. Abstr O-416. 3. Matthews. CROI 2021. Abstr 88.
4. niaid.nih.gov/diseases-conditions/long-acting-forms-hiv-prevention. 5. Hsu. Front. Immunol. 2021;12:2771. 6. Zhang. UKICRS 2020.
Abstr 77. 7. Matthews. J Acquir Immune Defic Syndr. 2021;88:314. 8. Begley. AIDS 2020. Abstr PEB0265. 9. Begley. CROI 2020. Abstr 470. Slide credit: clinicaloptions.com
Investigational
ARVs
Class Half-life Administration
Islatravir NRTTI
177-209 hr in
healthy adults7 Oral, implant
Lenacapavir
HIV capsid
inhibitor
7-11 wk SC8,
12 days oral9 Oral, SC
MK-8507 NNRTI
Mean apparent
terminal half-life:
~56-69 hr2
Oral

Islatravir: A New Potent and Long-Acting
Antiretroviral Agent
 Investigational NRTTI
 Potent antiviral activity with low in
vitro IC50 and activity against NRTI-
resistant HIV strains1
 Single-dose oral ISL associated with
reduction in plasma HIV-1 RNA
without emergence of viral resistance2
 Robust HIV-1 RNA decline associated
with ISL-TP concentrations
0.05 pmol/106 cells1
 Long ISL-TP half-life: 177-209 hr in
healthy adults1
1. Matthews. J Acquir Immune Defic Syndr. 2021;88:314. 2. Schürmann. Lancet. 2020;7:E164. 3. Schürmann. Lancet HIV 2020;7:e164. Slide credit: clinicaloptions.com
Days
HIV-1
RNA
Change
From
BL
(log
10
c/mL)
Virologic Response After Single Oral
Dose of Islatravir3
-2.5
-2.0
-1.5
-1.0
-0.5
0
0 2 4 6 8 10
ISL 0.5 mg
ISL 1 mg
ISL 2 mg
ISL 10 mg
ISL 30 mg

 Multinational, randomized, double-blind phase IIb trial in ART-naive adults with HIV-1 RNA ≥1000 copies/mL,
CD4+ cell count ≥200 cells/mL, CrCl ≥50 mL/min within 60 days prior to study treatment (N = 121)
 All participants with PDVF had confirmatory HIV-1 RNA levels <80 copies/mL
 5 of 7 patients with PDVF had an additional HIV-1 RNA level <50 copies/mL prior to changing to a new regimen
Phase II Dose-Ranging Trial of Daily Islatravir Plus
Doravirine: Virologic Outcomes at Wk 96
Molina. Lancet HIV 2021 e324. Molina. HIV Glasgow 2020. Abstr O415. Slide credit: clinicaloptions.com
HIV-1 RNA <50 copies/mL HIV-1 RNA ≥50 copies/mL No Virologic Data in Window
ISL 0.25 mg + DOR* (n = 29)
ISL 0.75 mg + DOR* (n = 30)
ISL 2.25 mg + DOR* (n = 31)
ISL + DOR combined* (n = 90)
DOR/3TC/TDF (n = 31)
Patients
(%)
86.2
6.9 6.9
90
6.7 3.3
67.7
16.1 16.1
81.1
10 8.9
0
20
40
60
80
100
80.6
6.5
12.9
Virologic Outcomes at Wk 96 by FDA Snapshot

Adverse Event Summary Through Wk 96
 A higher rate of drug-related AEs reported for DOR/3TC/TDF participants vs ISL
 No additional drug-related serious AEs were reported in any group during Wk 48-96
 2 patients in 2.25-mg ISL arm discontinued due to drug-related AEs (1 GI effects; 1 HBV reactivation)
 1 patient in DOR/3TC/TDF group discontinued due to drug-related AEs (worsening congenital long QT syndrome)
 Stable switch to oral DOR/ISL met primary efficacy endpoints at 48 wks vs continued 3-drug ART in phase III trials2
1. Molina. HIV Glasgow 2020. Abstr O415. 2. Merck press release, October 25, 2021; data have not yet been peer reviewed. Slide credit: clinicaloptions.com
Cumulative AEs Through Wk 96, n (^)1
ISL 0.25 mg
+ DOR
(n = 29)
ISL 0.75 mg
+ DOR
(n = 30)
ISL 2.25 mg
+ DOR
(n = 31)
ISL + DOR
Combined
(n = 90)
DOR/
3TC/TDF
(n = 31)
≥1 AE 25 (86.2) 27 (90.0) 22 (71.0) 74 (82.2) 27 (87.1)
Drug-related AE 0 3 (10.0) 4 (12.9) 7 (7.8) 7 (22.6)
Serious AE 1 (3.4) 3 (10.0) 1 (3.2) 5 (5.6) 3 (9.7)
Discontinued due to AE 1 (3.4) 0 2 (6.5) 3 (3.3) 1 (3.2)
Discontinued due to drug-related AE 0 0 2 (6.5) 2 (2.2) 1 (3.2)

MK-8507: Investigational Oral Once-Weekly NNRTI
5
1. Diamond. CROI 2021. Abstr 129. 2. Ankrom. HIV Glasgow 2020. Abstr O416. 3. NCT04564547. Slide credit: clinicaloptions.com
Antiviral Activity of MK-8507 Against
Clinical NNRTI Resistance Associated Variants
100
80
60
40
20
0
RPV
DOR
MK-8507
Fold
Change
in
IC
50
vs
Control
 MK-8507 structurally similar to DOR
and has similar resistance profile1
 Single-dose administration
associated with >1 log decline in
HIV-1 RNA at 7 days2
 PK support once-weekly dosing2
 Phase IIb 48-wk dose-ranging switch
study in patients suppressed on
BIC/FTC/TAF (planned N = 140)3
‒ Double-blinded, placebo-
controlled trial
‒ Once-weekly MK-8507 (100, 200
or 400 mg) + once-weekly ISL
(20 mg)

 Double-blind, randomized, placebo-controlled study of safety, tolerability, and PK of oral ISL in
adults at low-risk for acquiring HIV
 ISL-TP trough concentrations after 60 mg or 120 mg QM doses were above prespecified PK
threshold (0.05 pmol/106 PBMCs) infection
Phase IIa Study: Once-Monthly Oral Islatravir for PrEP
Hillier. HIV R4P 2021. Abstr 01363. Slide credit: clinicaloptions.com
Observed Mean (SD) ISL-TP Concentration-Time Profile in PBMCs
Overlaid on Population PK Model Simulated Median (95% CI) ISL-TP Concentrations in PBMCs
ISL-TP
Concentration
(pmol/10
6
PBMCs)
ISL-TP
Concentration
(pmol/10
6
PBMCs)
ISL 60 mg QM Dose ISL 120 mg QM Dose
Wk
28
0 4 8 12 16 20 24
102
101
100
10-1
10-2
PK threshold: 0.5 pmol/106 PBMC cells
Wk
28
0 4 8 12 16 20 24
102
101
100
10-1
10-2
PK threshold: 0.5 pmol/106 PBMC cells

Lenacapavir: Investigational First-in-class Long-Acting
HIV Capsid Inhibitor for Treatment and Prevention
 Small molecule which disrupts HIV capsid protein functions1
 High potency: Antiviral activity at very low doses (pM) and no cross-
resistance with approved drugs2
 Low in vivo systemic clearance1
 Slow-release kinetics from subcutaneous injection site1
1. Link. Nature. 2020;584: 614. 2. Begley. AIDS 2020. Abstr PEB0265. Slide credit: clinicaloptions.com

Lenacapavir Can Be Administered Both Subcutaneously
and Orally
 Adjustable dosing frequency
 Once every-6-mo dosing feasible
 Accumulation with repeated oral dosing
 Minimal food effect
 Once-weekly dosing feasible
1. Begley. AIDS 2020. Abstr PEB0265. 2. Begley. CROI 2020. Abstr 470. Slide credit: clinicaloptions.com
LEN Single Dose SC Formulation1 LEN Single Dose Oral Formulation2
LEN
(ng/mL)
LEN
(ng/mL)
100
10
0.1
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56
Wk Post Dose
6-fold paEC95 (IQ6)
300 mg (1 x 1 mL)
900 mg (3 x 1 mL)
900 mg (2 x 1.5 mL),
as administered in phase II/III
T1/2 = 7-11 wk
6 mo
(26 wk)
LEN
(ng/mL)
100
10
0.1
0
Wk Post Dose
1 2 3 4 5
6-fold paEC95 (IQ6)
T1/2 = 12 days
900 mg (3 tablets)
300 mg (1 tablet)
50 mg (1 tablet)

CAPELLA: Lenacapavir in Heavily ART–Experienced
Patients
1. Segal-Maurer. CROI 2021. Abstr 127. 2. Molina. IAS 2021. Abstr OALX01LB02. Slide credit: clinicaloptions.com
 4/11 patients tested had emergent capsid mutations conferring high level lenacapavir resistance: M66I
(n = 4), and 1 each of Q67H, K70N/R/S, N74D
P <.0001
Proportion of Participants on Functional Monotherapy
With Decline in HIV-1 RNA ≥0.5 log10 copies/mL at Day 15 Mean Change in HIV-1 RNA by Visit
100
80
60
40
20
0
21/24 2/12
88
17
Participants
(%)
Lenacapavir
(n = 24)
Placebo
(n = 12)
0.5
0
-0.5
-1
-1.5
-2
Change
in
HIV-1
RNA,
log
10
copies/mL
(%)
-2.5
Day
P < .0001
-0.29
-1.93
0 8 15
Placebo (n = 12)
Lenacapavir
(n = 24)

 No ISRs reported in 44% (32/72)
 56% (40/72) had ≥1 ISR related to LEN
‒ Most ISRs were grade 1 (70% [28/40])
and resolved within days
‒ 2 patients had grade 3 ISRs:
‒ 1 had swelling and erythema; resolved in
4 and 8 days, respectively; 1 had pain;
resolved in 1 day
‒ No grade 4 ISRs
‒ All nodules were grade 1
 All nodules were grade 1
 No discontinuations due to ISRs
CAPELLA: Injection-Site Reactions
Molina. IAS 2021. Abstr OALX01LB02. Slide credit: clinicaloptions.com
Incidence
Cumulative
Incidence, n (%)
Median
Duration, d
Swelling 19 (26) 11
Erythema 17 (24) 6
Pain 14 (19) 3
Nodule 13 (18) 153
Induration 9 (13) 71
Participants
(%)
Wk After First SC Injection
0
20
40
60
80
100
2 4 6 8 10 12 14 16 18 20 22 24 26 28
n = 72 72 67 59 55 46
72

 One participant in LEN SC + FTC/TAF 
BIC arm had emergent resistance
mutations at Wk 10
‒ CA: Q67H + K70R (LEN fold change = 20)
‒ RT: M184M/I
 Plasma LEN concentrations
consistently in target range
CALIBRATE: Long-Acting (Q6M) SC Lenacapavir in
Treatment-Naive Patients
Gupta. IAS 2021. Abstr OALB0302. Slide credit: clinicaloptions.com
Participants
(%)
100
80
40
60
20
0
HIV-1 RNA
<50 copies/mL
94
Virologic Outcomes at Wk 28 by FDA Snapshot (ITT)
n/N =
92 94
100
HIV-1 RNA
≥50 copies/mL
No Data
0 4 0 0
6 4 6
0
Group 1: LEN SC + FTC/TAF (→ TAF)
Group 2: LEN SC + FTC/TAF (→ BIC)
Group 3: LEN PO + FTC/TAF
Group 4: BIC/FTC/TAF
49/
52
49/
53
49/
52
25/
25
0/
52
2*/
53
0/
52
0/
25
3/
52
2/
53
3/
52
0/
25
*1 discontinuation due to not meeting a protocol criterion of HIV-1 RNA <50 c/mL
prior to Wk 28; 1 participant discontinued on Day 2.

Islatravir Plus Lenacapavir Combinations
 Randomized, open-label phase II study of safety/efficacy of QW oral ISL + LEN in suppressed patients
 Primary outcome: percentage of participants with HIV-1 RNA ≥50 c/mL at Wk 24 (FDA Snapshot)
 Secondary outcomes: HIV-1 RNA at Wk 12 and 48, TEAEs, PK
 Injectable ISL + LEN combination in development
NCT05052996. Slide credit: clinicaloptions.com
HIV-infected adults on
BIC/FTC/TAF ≥24 wk with
HIV-1 RNA <50 c/mL ≥24 wk
before and at screening
(planned N = 75)
Switch to ISL + LEN
ISL 40 mg + LEN 600 mg
on Days 1 and 2
(loading dose)
BIC/FTC/TAF
50/200/25 mg once daily
ISL 20 mg + LEN 300 mg
on Day 8, then weekly
Wk 48
Day 1 Day 8

bNAbs in Development for Treatment and Prevention of
HIV Infection
 VRCO1 and 3BNC117: target conserved region of CD4-binding site of HIV-1
envelope glycoprotein with broad in vitro neutralization capacity against all major
circulating HIV-1 subtypes1-4
1. Wu X. Science. 2010;329:856. 2. Mascola. Nat Med. 2000; 6:207.
3. Gautam R. Nature. 2016; 533:105. 4. Spencer. Front. Public Health. 2021;9:690017 Slide credit: clinicaloptions.com
Viral membrane
V1V2 Glycan
CD4 supersite
N332 glycan-V3 supersite
Glycans
Membrane-proximal
external region
gp120-gp41
interface
PGT121
PGT128
10-1074
DH270
PG9, PG16
PGT141-145
CAP256-VRC26
PGDM1400
CH01-04
VRC01, PG04, CH31,
3BNC117, CH103,
12A12, VRC13, VRC07
VRC07-523, N6, DH270,
BANC131, CH235
35022
PGT151
8ANC195
2F5
4E10
10E8V
HIV-1 Envelope Epitopes Targeted by bNAbs

ACTG A5340 and NIH15-I-0140: Effect of HIV bNAb
(VRCO1) on Viral Rebound After Treatment Interruption
 2 open-label phase I trials to assess
safety, PK properties, and antiviral
activity of VRC01 in PWH undergoing
ART interruption (N = 24)
 Results: No safety concerns
‒ VRC01 exerted pressure on
rebounding virus with selection for
preexisting and emerging antibody
neutralization-resistant virus
‒ VRC01 slightly delayed plasma viral
rebound but did not maintain viral
suppression by Wk 8
 Combinations of bNabs in progress:
‒ LEN (oral + SC) + 2 bNAbs: GS-5423
(3BNC 117) and GS-2872 (10 1074)
(IV) phase I safety 26-wk study in
suppressed patients (NCT 04811040)2
1 Bar. NEJM. 2016;375:2037. 2. NCT04811040. Slide credit: clinicaloptions.com
Plasma Viremia After ART Interruption1
A5340 Trial NIH Trial
Wk Since
Discontinuation of ART
0 4 8 14
106
105
103
102
101
Limit of
detection
2 6 10 12
Plasma
Viremia
(copies/mL)
Participants
A01
A02
A03
A04
A05
A06
A07
A08
A09
A10
A12
A13
A14
104
Wk Since
Discontinuation of ART
0 4 8 20
106
105
103
102
101
Limit of
detection
2 6 1012
Plasma
Viremia
(copies/mL)
Participants
A01
A02
A03
A04
A05
A06
A07
A08
A09
A10
104
141618

 Double-blind placebo-controlled phase I trial to assess safety and tolerability of a
single MK-8591 (54 mg or 62 mg) or placebo implant for 12 wk (N = 12)
Islatravir Implants: Intracellular ISL-TP PK
Threshold Maintained for Months
Barrett. Antimicrob Agents Chemother 2018;62:e01058. Matthew. IAS 2019. Abstr 4843. Slide credit: clinicaloptions.com
62 mg Implant
ISL-TP
(pmol/10
6
cells)
MK-8591-Plasma
(µM)
ISL-TP
(pmol/10
6
cells)
62 mg Implant: Simulations for 1 Yr
 62 mg implant will continue to release through 52 wk
 ISL-TP should be above threshold (0.05 pmol/106 cells) for >12 mo; projected concentration at 12 mo: 0.076 pmol/106
cells; projected time at which concentration falls below 0.05 pmol/106 cells: 68-70 wk (~16 mo)
 Implants in development also with TAF, cabotegravir
Relative Nominal Time (Wk)
0 5 10 15
10-3
10-2
10-1
100
101 Mean
Min and max of range
PK threshold: 0.05 pmol/106 cells
Removal of Implant
Wk
0 10 20 30
10-3
10-2
10-1
100
101
40 50
0
0.02
0.04
0.06
0.08
Projected Cweek52 ISL-TP:
~0.076 pmol/106 cells

Monthly Administration of Microneedle Array Patches
With Bictegravir
 Physiologically based PK modeling used to predict optimal BIC dosing by MAP in
100 simulated healthy persons
Kinvig. CROI 2021. Abstr. 377. Slide credit: clinicaloptions.com
Stratum corneum
Epidermis
Dermis
Microneedles
MAP
 600 µM height
 32.7 mg BIC
 8 cm² surface area
 16 x 16 Array

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Ключевые слайды по индивидуальному выбору АРТ / Key Slides on Individualized Choices in Antiretroviral Therapy.2021

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Ключевые слайды по индивидуальному выбору АРТ / Key Slides on Individualized Choices in Antiretroviral Therapy.2021