Современное лечение ВИЧ: новые подходы к оптимизации АРТ/Contemporary Management of HIV: Emerging Approaches to Optimize ART.2020

Contemporary Management of HIV:
Emerging Approaches to Optimize ART
This program is supported by an educational grant from ViiV Healthcare

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Core Faculty
Paul E. Sax, MD
Clinical Director
HIV Program and Division of Infectious Diseases
Brigham and Women's Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts

Program Directors
Joseph J. Eron, Jr., MD
Professor of Medicine and
Epidemiology
University of North Carolina
School of Medicine
Director, AIDS Clinical Trials Unit
University of North Carolina
Chapel Hill, North Carolina
Princy N. Kumar, MD, FIDSA,
MACP
Professor of Medicine and
Microbiology
Chief, Division of Infectious Diseases
and Travel Medicine
Senior Associate Dean of Students
Georgetown University School of
Medicine
Washington, DC

Faculty Disclosures
Joseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from
Gilead Sciences, Janssen, Merck, and ViiV Healthcare and funds for research
support from Gilead Sciences, Janssen, and ViiV Healthcare.
Princy N. Kumar, MD, FIDSA, MACP, has disclosed that she has received
consulting fees from Amgen, Gilead Sciences, GlaxoSmithKline, Merck, and
Theratechnologies; has received funds for research support from Gilead
Sciences, GlaxoSmithKline, Merck, and Theratechnologies; and has ownership
interest in Gilead Sciences, GlaxoSmithKline, Johnson & Johnson, Merck, and
Pfizer.
Paul E. Sax, MD, has disclosed that he has served as a consultant or on a
scientific advisory board for Gilead Sciences, GlaxoSmithKline/ViiV, Janssen,
and Merck and that he has received funds for research support from Gilead
Sciences, GlaxoSmithKline/ViiV, and Merck.

Outline
 Case-Based Discussion: Emerging Approaches to Optimize ART
‒ Rapid ART
‒ Evolving Issues in Combination Therapy
‒ Evolving Options for Switch Therapy
 Integrating a New PrEP Option

Case Patient: Newly Diagnosed Older Woman
 An asymptomatic 54-yr-old woman was found positive on 4th
generation and confirmatory HIV screening test
 She has a past medical history of hypertension, diabetes, and obesity;
current medications are losartan, amlodipine, and metformin
 She is immediately referred to your clinic for care; aside from a BMI of
32, she has a normal physical examination
 You order the following from the laboratory: CBC; CMP; hepatitis A, B,
and C serologies; CD4+ cell count; plasma HIV-1 RNA; HIV resistance
genotype; HLA-B5701 genotype
 After further discussion, she wants to start treatment right away

 Systematic review of ART initiation within 14 days of eligibility determination
across 4 randomized clinical trials
‒ Compared with standard care, same-day ART increased likelihood of ART initiation in
first 90 days, patient retention, and viral suppression at 12 mos
Improved Clinical Outcomes With Rapid ART Initiation
Ford. AIDS. 2018;32:17.
Characteristic
ART start within 90 days
Retained in care at 12 mos
Viral suppression at 12 mos
LTFU at 12 mos
Died by 12 mos
.2 1 3
Standard Care Same Day ART
2
RR (95% CI)
1.35 (1.13-1.62)
1.11 (0.99-1.26)
1.17 (1.07-1.27)
0.66 (0.42-1.04)
0.53 (0.28-1.00)

Pilot Study: Rapid ART Program Initiative for HIV
Diagnoses (RAPID) in San Francisco
 Same-day (RAPID) ART initiation, including
access to HIV provider, labs, counseling
‒ Loss to follow-up similar in RAPID protocol
vs non-RAPID protocol patients (10.3% vs
14.9%)
 Compared with 2010-2013, when
different ART initiation strategies were in
place, RAPID protocol led to faster HIV-1
RNA suppression (median: 1.8 vs 4.3 mos;
P = .0001)
Time to Viral Suppression in Patients Newly Diagnosed
HIV+ at UCSF With RAPID vs Prior Periods
Pilcher. JAIDS. 2017;74:44.
RAPID ART intervention period, 2013-2015
Universal ART guidelines period, 2010-2013
CD4-guided ART period, 2006-2009
1.00
0.75
0.50
0.25
0
ProportionWithHIV-1RNA
<200copies/mL
0 10 20 30
Mos From Clinic Referral

Ward 86 RAPID ART Program: Time to Virologic
Suppression
PatientsWithHIV-1RNA<200c/mL(%)
Ever achieving
HIV-1 RNA < 200 c/mL
at 1 yr after ART start
HIV-1 RNA < 200 c/mL at
last recorded assessment
Yrs Since ART Start
100
75
50
25
0
0 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 2.25 2.50 2.75 3.00
95.8
%
91.2
%
Coffey. AIDS. 2019;33:825.
 Retrospective analysis on 216 out of 225 patients (96%) referred to RAPID program from 2013-2017

Current Recommendations for Same-Day ART
1. DHHS Guidelines. 2019. 2. WHO Guidelines. July 2017. 3. Saag. JAMA. 2018;320:379.
WHO[2]
 Recommended
where feasible
IAS-USA[3]
 Start ART as soon as
possible, including
immediately after
diagnosis, if patient is
ready
DHHS[1]
 Initiate ART
immediately (or as
soon as possible) after
HIV diagnosis

DHHS Regimen Recommendations for Rapid ART
Recommended Regimens
BIC/TAF/FTC
DTG + (TAF or TDF) + (3TC or FTC)
(DRV/RTV or DRV/COBI) + (TAF or TDF) + (3TC or FTC)
Regimens Not Recommended
NNRTI-based regimens or DTG/3TC
due higher rate of transmitted NNRTI and NRTI
vs PI or INSTI drug resistance
Regimens requiring ABC
until HLA-B*5701 test results received
DHHS Guidelines. 2019.

Evolving Issues in First-line
Combination Therapy

Key Clinical Questions: First-line Combination Therapy
 Can 2-agent regimens be as effective as those with 3+ drugs for
first-line therapy?
‒ Which regimens have the most compelling data?
 How should we be considering new weight gain data?
 What are the latest recommendations regarding DTG use in persons of
childbearing potential?

Case Patient: Newly Diagnosed Woman Inquiring About
Simple, Once-Daily Options
 A 28-yr-old asymptomatic woman presents to your clinic after recently being
diagnosed with HIV
 Her physical examination is unremarkable, and she has no comorbid conditions
 Laboratory information:
‒ Normal CBC and renal function
‒ Hepatitis A, B, and C negative
‒ HIV-1 RNA 22,000 copies/mL, CD4+ cell count 510 cells/mm3
‒ Wild-type HIV
 She is interested in a simple, once-daily option

GEMINI-1 and -2: DTG + 3TC Noninferior to DTG + FTC/TDF
in Treatment-Naive Patients at Wk 96
 Parallel, international, randomized, double-blind phase III studies (N = 1433)
 No treatment-emergent resistance observed in patients with CVW
*Adjusted for BL HIV-1 RNA, BL CD4+ cell count, and study.
Endpoint, % (n)
DTG + 3TC
(n = 716)
DTG + FTC/TDF
(n = 717)
Difference,* %
(95% CI)
Responders 86.0 (616) 89.5 (642) -3.4 (-6.7 to 0)
HIV-1RNA<50copies/mL,
%(95%CI)
100
80
60
40
20
0
0 4 8 12 16 24 36 48 60 72 84 96
Wk
87.0
93.2 91.5 87.2 86.0
89.589.4
93.393.4
84.4
Cahn. J Acquir Immune Defic Syndr. 2019;[Epub]. Slide credit: clinicaloptions.com

GEMINI-1 and -2: Virologic Response at Wk 96 by
Baseline HIV-1 RNA and CD4+ Cell Count
FDA Snapshot Analysis TRDF Analysis*
> 100,000≤ 100,000
BL HIV-1 RNA,
copies/mL
> 200 ≤ 200
BL CD4+ Cell Count,
cells/mm3
> 200 ≤ 200
BL CD4+ Cell Count,
cells/mm3
BL HIV-1 RNA,
copies/mL
499/
576
510/
564
117/
140
132/
153
573/
653
594/
662
43/
63
48/
55
560/
576
545/
564
132/
140
146/
153
633/
653
638/
662
59/
63
53/
55
n/N =
DTG + 3TC DTG + FTC/TDF
*Accounts for CVW, withdrawal for lack of efficacy or treatment-related AEs, and participants meeting protocol-defined stopping criteria.
PatientsWithHIV-1RNA
<50copies/mL(%)
100
80
60
40
20
0
87 90
84 86 88 90
68
87
PatientsWithoutTRDF(%)
n/N =
100
80
60
40
20
0
97 97 9794 9495 96 96
Cahn. J Acquir Immune Defic Syndr. 2019;[Epub]. Cahn. IAS 2019. Abstr WEAB0404LB.
> 100,000≤ 100,000

 Multicenter, open-label, randomized phase IV study (N = 145)
‒ Baseline: 24% HIV-1 RNA > 100,000 c/mL
 No significant difference in AEs leading to d/c, serious AEs, or deaths between arms
ANDES: DRV/RTV + 3TC Noninferior to Triple ART in
Treatment-Naive Patients at Wk 48
Figueroa. CROI 2018. Abstr 489.
DRV/RTV + 3TC
DRV/RTV + 3TC/TDF
Treatment Difference
All patients: -1.0% (95% CI: -7.5% to 5.6%)
Patients with high BL HIV-1 RNA: -1.4%
(95% CI: -17.2% to 14.4%)
 1 virologic failure with DRV/RTV + TDF/3TC
ITT:HIV-1RNA
<50c/mL(%)
n/N = 70/75 66/70
93 9194 92
0
20
40
60
80
100
All Patients Patients With BL
HIV-1 RNA > 100,000
c/mL (n = 35)

DHHS Recommendations on the Use of 2-Drug
Regimens in First-line ART
 DTG/3TC now among Recommended Initial Regimens for Most People
with HIV
‒ Except: if HIV-1 RNA > 500,000 copies/mL, HBV coinfection, or if starting
ART before HIV NRTI resistance or HBV test results are available
2-Drug Option Limitations
DRV/RTV + RAL Only if HIV-1 RNA < 100,000 copies/mL and CD4+ cell count > 200 cells/mm3
DRV/RTV + 3TC Limited randomized trial data to date
DTG/3TC Only if HIV-1 RNA < 500,000 copies/mL, no HBV coinfection, and no RT
resistance

ADVANCE: Mean Change in Weight by Sex
 Significantly greater weight increase with DTG vs EFV, with TAF vs TDF at Wk 96;
plateauing in weight gain after Wk 48 observed in men but not in women
Wk
Women
MeanWeightChange(kg)
Men
4
2
0
0 4 12 24 36
10
8
6
12
48 60 72 84 96
14
n = 430 418 402 387 376 374 366 292 232 140
+5 kg
+4 kg
+1 kg
NS
WkMeanWeightChange(kg)
4
2
0
0 4 12 24 36
10
8
6
12
48 60 72 84 96
DTG + FTC/TAF
DTG + FTC/TDF
EFV + FTC/TDF
14
n = 549 531 514 488 474 459 441 359 276 175
+10 kg
+5 kg
+3 kg
P<.05P<.001
P<.01
P<.001
P<.01
Hill. IAS 2019. Abstr MOAX0102LB.

*
*
Multivariate Analysis of Weight Gain Following ART
Initiation in RCTs
 Pooled analysis of weight gain across 8 randomized phase III clinical
trials of first-line ART initiation occurring in 2003-2015 (N = 5680)
*Color-coded to match respective comparators, denoting P ≤ .05 vs NNRTI (first panel), EVG/COBI (second panel), or ZDV (last panel).
TAF
ABC
TDF
ZDV
BIC
DTG
EVG/COBI
INSTI
PI
NNRTI
1
0
4
3
LSMeanWeightΔ,kg(95%CI)
Wks
12 24 36 48 60 72 84 96
2
*
*
* *
* *
**
Wks
12 24 36 48 60 72 84 96
6
0
5
4
3
2
1
Wks
12 24 36 48 60 72 84 96
6
0
5
4
3
2
1
*
*
*
*
*
*
*
*
*
* *
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
Sax. Clin Infect Dis. 2019;[Epub].

INSTIs and TAF Associated With Greater Weight Gain vs
Other ARVs
OR (95% CI)
P Value
.82
.44
.31
.003
.034
.003
.73
.026
.035
.002
ABC vs ZDV
TDF vs ZDV
TDF vs ABC
TAF vs TDF
TAF vs ZDV
TAF vs ABC
ATV/RTV vs EFV
EVG/COBI vs EFV
RPV vs EFV
BIC or DTG vs EFV
4-2 -1 0 1 2 3
Decreased Risk Increased Risk
Sax. Clin Infect Dis. 2019;[Epub].
Risk of Weight Gain ≥ 10%[1]

DHHS Guidelines: Weight Gain and ART
 New guidelines recognize weight gain as a common and/or severe AE
associated with ART
 Further clarification is needed on distribution of weight gain, if it is
associated with cardiometabolic risk, and if it is reversible upon
discontinuation of the offending agent
“Weight gain has been associated with initiation of ART and
subsequent viral suppression. The increase appears to be
greater with INSTIs than with other drug classes. Greater
weight increase has also been reported with TAF than with
TDF, and greater with DOR than EFV.”

DHHS Recommendations Before Initiating an INSTI in
Person of Childbearing Potential
 A pregnancy test should be performed
 “To enable individuals of childbearing potential to make informed decisions, providers
should discuss the benefits and risks of using DTG around the time of conception, including
the low risk of NTDs and the relative lack of information on the safety of using other
commonly prescribed ARV drugs, including other INSTIs, around the time of conception”
Persons of Childbearing Potential Initiating ART
 Using effective contraception: DTG is a recommended option
 Sexually active, not planning to conceive, not using contraception: DTG is an
alternative option (consider similar approach for BIC)
 Trying to conceive: Initiate a regimen preferred during pregnancy: RAL, ATV/RTV,
or DRV/RTV + TDF/FTC, TDF/3TC, or ABC/3TC; DTG is an alternative option
Slide credit: clinicaloptions.comDHHS Guidelines. 2019.

IMPAACT 2010: Safety and Efficacy of DTG vs EFV and
TDF vs TAF in Pregnancy
 Randomized, open-label phase III trial in pregnant women with HIV at 14-28 wks of gestational age
 Neonatal death more frequent with EFV/FTC/TDF (4.8%) vs DTG + FTC/TAF (1.0%; P = .019) or
DTG + FTC/TDF (1.5%; P = .053)
 2 infants diagnosed with HIV in DTG + FTC/TAF arm (maternal delivery HIV-1 RNA 58,590 c/mL) and
1 infant diagnosed with HIV in DTG + FTC/TDF arm (maternal delivery HIV-1 RNA < 40 c/mL)
Chinula. CROI 2020. Abstr 130LB. Slide credit: clinicaloptions.com
Delivery HIV-
1 RNA
< 200 c/mL,*
%
DTG
Arms
EFV/FTC/TDF
Risk
Difference, %
(95% CI)
P
Value
ITT
population
97.5 91.0 6.5 (2.0-10.7) .005
PP
population
97.5 91.4 6.0 (1.6-10.3) .008
Adverse Pregnancy
Outcomes†, %
DTG +
FTC/TAF
(n = 217)
DTG +
FTC/TDF
(n = 215)
EFV/FTC/
TDF
(n = 211)
Any adverse pregnancy
outcome
24.1‡ 32.9 32.7
Preterm delivery 5.8§ 9.4 12.1
Small for gestational age 16.3 22.5 20.5
Stillbirth‡ 3.7 5.2 1.9
*Median antepartum follow-up: 17.4 wks.†Median gestational age at time of ART initiation: 21.9 wks. ‡P = .043 vs DTG + FTC/TDF and P = .047 vs
EFV/FTC/TDF. §P = .023 vs EFV/FTC/TDF.

Evolving Switch Therapy Options

Case Patient: Receiving DTG/ABC/3TC, Develops
Coronary Disease
 A 57-yr-old man presented with candida esophagitis approximately 10 yrs
ago when diagnosed with HIV
‒ Treatment with DRV/RTV + FTC/TDF led to undetectable HIV-1 RNA and CD4+
cell count between 300 and 450 cells/mm3
‒ Switched to DTG/ABC/3TC in 2017 which he has tolerated well
 Current medications
‒ Metformin for diabetes mellitus
‒ Benazepril for hypertension (reasonably controlled)
 Recently admitted to the hospital with chest pain, underwent angioplasty for
coronary disease

Emerging Strategies for Switch Therapy
 DTG/RPV approved for virologically suppressed patients with no history
of treatment failure and no resistance to DTG or RPV
 DTG/3TC approved for initial therapy in patients with no resistance to
DTG or 3TC
 DRV/RTV + 3TC
 DRV/RTV + DTG
 Long-acting injectable therapy with cabotegravir + RPV
DHHS Guidelines. December 2019. Slide credit: clinicaloptions.com

SWORD-1 and -2: Switch to DTG + RPV vs Continuation
of Baseline ART in Virologically Suppressed Adults
 Parallel, randomized, open-label, multicenter phase III noninferiority studies[1,2]
 Primary endpoint: HIV-1 RNA < 50 copies/mL maintained in 95% of patients in each arm at
Wk 48; adjusted treatment difference: -0.2% (95% CI: -3.0 to 2.5)[2]
 10/990 (1%) confirmed virologic withdrawals through Wk 100: Treatment-emergent NNRTI
resistance mutations documented in 3/10, all from early switch arm
Switch to DTG + RPV
(n = 513)
Continue Baseline ART
(n = 511)
Switch to DTG + RPV
Continue DTG + RPV
Early Switch Phase
1. Aboud. AIDS 2018. Abstr THPEB047. 2. Llibre. Lancet. 2018;391:839. Slide credit: clinicaloptions.com
Adults on stable ART (INSTI,
NNRTI, or PI + 2 NRTIs) with
HIV-1 RNA < 50 c/mL for ≥ 6
mos at screening; no
previous VF or HBV
infection; no DTG or RPV
resistance
(N = 1024)
Late Switch Phase
Wk 148Wk 52 Wk 100Wk 48
Wk 100 Virologic Response
by FDA Snapshot
89%
93%
(HIV-1 RNA < 50 c/mL)

Difference (%)
-3.4
0.2
-8 -6 -4 -2 0 2 4 6 8
3.9
Key Secondary Endpoint
(HIV-1 RNA < 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
-8% NI
margin
TANGO: Switch to DTG/3TC vs Continuing TAF-Based
ART in Virologically Suppressed Adults
 International, randomized, open-label
phase III study in patients with no
prior VF, NRTI or INSTI resistance
TAF-Based ARTDTG/3TC
TAF-Based ART DTG/3TC
-1.2 0.7
-0.3
-8 -6 -4 -2 0 2 4 6 8
Patients(%)
100
80
40
60
20
0
HIV-1 RNA
≥ 50 c/mL
HIV-1 RNA
< 50 c/mL
No Virologic
Data
0.3 0.5
93.2 93.0
6.5 6.5
Switch to DTG/3TC
(n = 369)
Continue TAF-based ART
(n = 372)
FDA Snapshot at Wk 48 (ITT-E)
Adjusted Treatment Difference (95% CI)*
Primary Endpoint
(HIV-1 RNA ≥ 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
4% NI
margin
*Adjusted for baseline third agent class.
van Wyk. Clin Infect Dis. 2020;[Epub].

DUAL-GESIDA: Maintenance DRV/RTV + 3TC vs
DRV/RTV + 2 NRTIs
 Randomized, open-label, multicenter phase IV trial in which virologically suppressed patients
switched to DRV/RTV + 3TC or continued on DRV/RTV + 2 NRTIs (N = 257)
Pulido. Clin Infect Dis. 2017;65:2112. Pulido. HIV Glasgow 2016. Abstr O331.
Wk 48 Virologic Efficacy
HIV-1 RNA
< 50 c/mL
No Data
100
80
60
40
20
0
Patients(%)
89
93
3 2
8 6
Treatment difference: -3.8%
(95% CI: -11.0% to 3.4%)
DRV/RTV + 3TC (n = 126)
Continued ART (n = 123)
HIV-1 RNA
≥ 50 c/mL
 No resistance detected for 2 patients with
resistance data in dual arm
 Similar rates of AEs between arms
 Discontinuation for AEs: 0.8% dual vs 1.6%
triple ART (P = .55)

ATLAS and FLAIR: Long-Acting Intramuscular CAB + RPV
After Initial Virologic Suppression With Oral Therapy
 Multicenter, randomized, open-label phase III noninferiority trials
 Primary endpoint for both trials: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA Snapshot in ITT-E
LA CAB 400 mg + RPV 600 mg IM Q4W
(n = 303)
Continue Baseline ART
(n = 308)
Adults on stable ART (either
first or second regimen) with
HIV-1 RNA < 50 copies/mL for
≥ 6 mos with no previous VF
(N = 616)
Comparator arm
patients eligible to
receive CAB + RPV
in extension phase
after Wk 52
(ATLAS-2M study)
Wk 48 Primary Endpoint
ATLAS
LA CAB 400 mg +
RPV 600 mg IM Q4W
(n = 278)
Continue DTG/ABC/3TC PO QD
(n = 283)
ART-naive patients with
HIV-1 RNA ≥ 1000 copies/mL,
HBsAg negative, no NNRTI RAMs
but K103N permitted
(N = 629)
CAB 30 mg +
RPV 25 mg PO QD
(n = 283)
Wk 48 Primary EndpointWk 4
DTG/ABC/3TC PO QD
Wk 96Day 0
Wk 20FLAIR
1. Swindells. NEJM. 2020;382:1112. 2. Orkin. NEJM. 2020;382:1124.
CAB 30 mg +
RPV 25 mg PO QD
(n = 308)
Wk 4Day 0

-1.2 2.5
0.6
-10 -8 -6 -4 -2 0 2 4 6 8 10
ATLAS: Switch to Long-Acting CAB + RPV vs Continued
3-Drug ART in Virologically Suppressed Adults
Patients(%)
Difference (%)
Difference (%)
100
80
40
60
20
0
1.6 1.0
92.5 95.5
5.8 3.6
LA CAB + LA RPV
(n = 308)
Continued BL ART
(n = 308)
-6.7
-3.0
-10 -8 -6 -4 -2 0 2 4 6 8 10
0.7
Adjusted Treatment Difference (95% CI)*
(HIV-1 RNA < 50 copies/mL)
LA CAB + LA RPV noninferior
to continued BL ART
Primary Endpoint
(HIV-1 RNA ≥ 50 copies/mL)
to continued BL ART
6% NI
margin
-10% NI
margin
*Adjusted for sex and
BL third agent class.
Virologic Outcomes at Wk 48
Virologic
Nonresponse
(≥ 50 c/mL)
Virologic
Success
(< 50 c/mL)
No Virologic
Data
Continued ARTLA CAB + LA RPV
Continued ART LA CAB + LA RPV
Swindells. NEJM. 2020;382:1112.

-2.8 2.1
-0.4
6% NI
margin
-10 -8 -6 -4 -2 0 2 4 6 8 10
Difference (%)
Difference (%)
Patients(%)
100
80
40
60
20
0
Virologic
Nonresponse
(≥ 50 c/mL)
Virologic
Success
(< 50 c/mL)
2.1 2.5
93.6 93.3
4.2 4.2
LA CAB + LA RPV
(n = 283)
DTG/ABC/3TC
(n = 283)
-10% NI
margin
Difference (%)
-3.7
0.4
-10 -8 -6 -4 -2 0 2 4 6 8 10
4.5
Virologic Outcomes at Wk 48 Adjusted Treatment Difference (95% CI)*
DTG/ABC/3TCLA CAB + LA RPV
DTG/ABC/3TC LA CAB + LA RPV
(HIV-1 RNA < 50 copies/mL):
to DTG/ABC/3TC
*Adjusted for sex, BL HIV-1
RNA (< vs ≥ 100,000 c/mL).
FLAIR: Long-Acting CAB + RPV Maintenance After Oral
DTG/ABC/3TC Induction
Primary Endpoint
(HIV-1 RNA ≥ 50 copies/mL)
to DTG/ABC/3TC
No Virologic
Data
Orkin. NEJM. 2020;382:1124.

ATLAS and FLAIR: Treatment-Emergent Resistance With
Long-Acting CAB + RPV
 101/483 patients had BL L74I in FLAIR: n = 64 from Russia, n = 60 with subtype A[3]
‒ Presence of this polymorphism did not negatively affect proportion achieving HIV-1
RNA < 50 copies/mL at Wk 48
1. Swindells. CROI 2019. Abstr 139. 2. Orkin. CROI 2019. Abstr 140LB. 3. Overton. IAS 2019. Abstr MOPEB257. Slide credit: clinicaloptions.com
Study Sex Country
HIV-1
Subtype
Wk of
Failure
NNRTI RAMs INSTI RAMs*
Baseline Failure Baseline Failure
ATLAS[1]
F Russia A/A1 8 E138E/A E138A L74I L74I
F France AG 12 V108V/I, E138K V108I, E138K None None
M Russia A/A1 20 None E138E/K L74I L74I, N155H
FLAIR[2]
F Russia A1 20 None E138E/A/K/T L74I L74I, Q148R
M Russia A1 28 None K101E L74I L74I, G140R
F Russia A1 48 None E138K L74I L74I, Q148R
*L74I not considered an INSTI RAM by IAS-USA guidance; not expected to affect CAB sensitivity.

ATLAS and FLAIR: Patient-Reported Preference for Drug
Delivery in Patients Receiving Long-Acting CAB + RPV
1. Swindells. CROI 2019. Abstr 139. 2. Swindells. NEJM. 2020;382:1112. 3. Orkin. CROI 2019. Abstr 140LB. 4. Orkin.
NEJM. 2020;382:1124. Slide credit: clinicaloptions.com
*Per single question in Wk 48 participant survey.
Study Population
Preferred Regimen,* % (n/N)
Long-Acting IM Daily PO
ATLAS[1,2]
 ITT-E 86 (266/308) 2 (7/308)
 Responding participants 97 (266/273) --
FLAIR[3.4]
 ITT-E 91 (257/283) 1 (2/283)
 Responding participants 99 (257/259) --

ATLAS-2M: Cabotegravir + Rilpivirine IM Q8W vs Q4W
Overton. CROI 2020. Abstr 34. NCT03299049.
 Multicenter, randomized, open-label phase III noninferiority trial
CAB LA 600 mg + RPV LA 900 mg IM Q8W
(n = 522)
CAB LA 400 mg + RPV LA 600 mg IM Q4W
(n = 523)
2 populations: adults from
ATLAS receiving either CAB LA
+ RPV LA Q4W* or SoC ART
and patients receiving SoC
ART outside of ATLAS†
(N = 1045)
*Participants transitioning from ATLAS must have been on CAB LA + RPV LA Q4W or a current ART regimen through at least Wk 52 and had HIV-1 RNA < 50 c/mL
at screening. †SoC participants not transitioning from ATLAS study on uninterrupted current regimen (initial or second combined ART) for ≥ 6 mos prior to
screening and documented evidence of ≥ 2 plasma HIV-1 RNA < 50 c/mL in 12 mos prior to screening (one 6-12 mos and one within 6 mos prior to screening).
Participants excluded if history of VF or if prior genotype results show any major INSTI or NNRTI mutations (except K103N).
Option to
continue
CAB LA +
RPV LA
Q4W or
Q8W after
Wk 100
Oral CAB
30 mg +
RPV 25
mg QD
(except ATLAS
participants
on LA tx)
Wk 48 Primary
EndpointWk 4 Wk 96 Wk 100
 Primary endpoint: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA snapshot in ITT-E
 Secondary endpoints: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA snapshot in ITT-E,
safety and tolerability, VF, resistance, and treatment preference
Stratified by prior
CAB + RPV exposure

ATLAS-2M: Virologic Outcomes at Wk 48 in ITT-E by FDA
Snapshot
Slide credit: clinicaloptions.comOverton. CROI 2020. Abstr 34.
Q4WQ8W
Difference (%)
-0.6 2.2
0.8
4% NI
margin
Difference (%)
-2.1 3.7
0.8
Q8WQ4W
-10% NI
margin
Primary endpoint
(HIV-1 RNA ≥ 50 c/mL):
CAB LA + RPV LA Q8W
noninferior to Q4W
Key secondary endpoint
(HIV-1 RNA < 50 c/mL):
CAB LA + RPV LA Q8W
noninferior to Q4W
CAB LA + RPV LA Q8W
(n = 522)
CAB LA + RPV LA Q4W
(n = 523)
Adjusted Treatment Difference (95% CI)*Virologic Outcomes
*Based on Cochran-Mantel-Haenszel analysis adjusting for prior CAB + RPV exposure.
100
80
60
40
20
0
Participants(%)
Virologic
Nonresponse
(≥ 50 c/mL)
Virologic
Success
(< 50 c/mL)
No Virologic
Data
1
5.5
94.3 93.5
-10 -8 -6 -4 -2 0 2 4 6 8 10
-10 -8 -6 -4 -2 0 2 4 6 8 10
1.7 4.0

 CAB LA + RPV LA well tolerated
‒ 98% of ISRs were grade 1/2;
median duration was 3 days
 Patients preferred CAB LA +
RPV LA over oral therapy
 Patients previously receiving
CAB LA + RPV LA preferred Q8W
dosing over Q4W dosing
ATLAS-2M: Virologic Failure, ISRs, Patient Preferences
Slide credit: clinicaloptions.comOverton. CROI 2020. Abstr 34.
Outcome
CAB LA + RPV LA
Q8W
(n = 522)
CAB LA + RPV LA
Q4W
(n = 523)
CVF, n (%) 8 (1.5) 2 (0.4)
CVF with RPV
RAMs,* n/N
6/8 1/2
Treatment-
emergent RPV
RAMs
K101E, E138E/K,
E138A, Y188L
K101E, M230L
CVF with INSTI
RAMs,* n/N
5/8 2/2
Treatment-
emergent INSTI
RAMs
Q148R, N155H† E138E/K,Q148R,
N155N/H
*Post hoc BL PBMC HIV-1 DNA testing. †Or a mixture.

Survey: Preferences on Mode of ART Administration in
Treatment-Experienced Patients
 Survey of patients with HIV in North and South Carolina (N = 263, mean 12 yrs on ART, 59%
on single-pill daily ART)
– Greater interest in injection in those with higher education or younger age
Compared with your current HIV medicines, how interested would you be in
switching to a new treatment that involves . . .
A single pill taken once per wk
2 shots given in clinic every other month
2 small plastic implants in the forearm every 6 months
Somewhat
Interested
Very
Interested
58
38
14
20
23 23
66
39
18
100
80
60
40
20
0
Patients(%)
Not at All
Interested
Slide credit: clinicaloptions.comDerrick. Open Forum Infectious Diseases. 2018;5:10.

FDA-Approved HIV PrEP Regimens
1. Emtricitabine/tenofovir DF PI. 2. Tenofovir AF/emtricitabine PI. 3. Saag. JAMA. 2018;320:379. Slide credit: clinicaloptions.com
 Once-daily* oral FTC/TDF indicated in combination with safer sex
practices for HIV-1 PrEP to reduce the risk of sexually acquired HIV-1[1]
 Once-daily oral FTC/TAF indicated for PrEP to reduce the risk of HIV-1
infection from sexual acquisition, excluding individuals at risk from
receptive vaginal sex (risk from receptive vaginal sex excluded because
effectiveness in this population has not yet been evaluated)[2]
*IAS-USA guidelines include optional recommendation for on-demand FTC/TDF use for MSM
with infrequent sex (2-1-1 dosing): Double dose before sex, 1 dose 24 hrs after first dose, 1 dose
48 hrs after first dose[3]

DISCOVER: Efficacy, Safety of FTC/TAF vs FTC/TDF Oral
PrEP in cis-MSM and Transgender Women
 Randomized, double-blind phase III noninferiority trial in Europe and North America
 Primary endpoint: HIV incidence/100 PY (noninferiority upper bound of 95% CI for IRR of
FTC/TAF vs FTC/TDF: < 1.62; expected incidence 1.44/100 PY based on prior studies)
 FTC/TAF noninferior to FTC/TDF for primary endpoint of HIV incidence/100 PY
‒ Wk 48: 0.16 vs 0.34 (IRR: 0.47; 95% CI: 0.19-1.15)[2]
‒ Wk 96: 0.16 vs 0.30 (IRR: 0.54; 95% CI: 0.23-1.26)[3]
1. Ogbuagu. CROI 2020. Abstr 92. 2. Hare. CROI 2019. Abstr 104LB. 3. Ruane. EACS 2019. Slide credit: clinicaloptions.com
cis-MSM and TG women at high risk
of HIV (≥ 2 episodes of condomless
anal sex in past 12 wks or rectal
gonorrhea/chlamydia or syphilis in
past 24 wks), HBV negative, and
eGFR ≥ 60 mL/min
(N = 5387)
Open-label
switch
FTC/TAF QD
(n = 2694)
FTC/TDF QD
(n = 2693)
Current Analysis[1]:
Wk 96
FTC/TDF QD
FTC/TAF QD
Wk 144Wk 48

DISCOVER: Wk 96 Renal Safety
 In bone safety substudy (n = 375), hip and spine BMD changes significantly more
favorable with FTC/TAF vs FTC/TDF (P < .001) in overall groups
Ogbuagu. CROI 2020. Abstr 92. Slide credit: clinicaloptions.com
Wk 96 Renal Outcome FTC/TAF (n = 2694) FTC/TDF (n = 2693) P Value
Median change from baseline in eGFRCG, mL/min -0.6 -4.1 < .001
Renal discontinuations, n 2 6 NA
Fanconi syndrome, n 0 1 NA
Mean % BMD Change
From Baseline
Spine Hip
FTC/TAF FTC/TDF P Value FTC/TAF FTC/TDF P Value
Wk 48 +0.5 (n = 159) -1.1 (n = 160) < .001 +0.2 (n = 158) -1.0 (n = 158) < .001
Wk 96 +1.0 (n = 144) -1.4 (n = 140) < .001 +0.6 (n = 140) -1.0 (n = 137) < .001

DISCOVER: Categorical BMD Changes at Wk 96
Categorical BMD Change at Wk 96, % FTC/TAF FTC/TDF P Value
Change in spine BMD from BL
 ≥ 5% increase
 ≥ 3% to < 5% increase
 ≥ 3% to < 5% decrease
 ≥ 5% decrease
10
13
7
4
4
3
13
16
.047
< .001*
< .001*
< .001
Change in hip BMD from BL
 ≥ 7% increase
 ≥ 3% to < 7% increase
 ≥ 3% to < 7% decrease
 ≥ 7% decrease
3
14
7
0
1
5
20
1
.22
.007*
< .001*
.16
Ogbuagu. CROI 2020. Abstr 92.
*P values for ≥ 3% change also includes ≥ 5% change for spine and ≥ 7% change for hip.

DISCOVER: Wk 96 Lipid, Glucose, Weight, and
BMI Outcomes
 Decreases in total, LDL, and HDL cholesterol significantly greater with FTC/TDF vs FTC/TAF (P < .001
for each); triglycerides increased with FTC/TAF and decreased with FTC/TDF (P < .001)
‒ No significant difference in fasting glucose between PrEP regimens
Ogbuagu. CROI 2020. Abstr 92. Slide credit: clinicaloptions.com
Body Weight BMI
FTC/TAF FTC/TDF
P < .001
P < .001
Wk Wk
MedianBodyWeightChange
FromBL,kg(Q1,Q3)
MedianBMI,kg/m2(Q1,Q3)
6
-3
3
0
0 12 24 36 48 60 72 84 96
+1
+0
+1.7
+0.5
30
22
28
24
0 12 24 36 48 60 72 84 96
25.6
25.3
25.9
25.4
26 25.3
25.3

Considerations for Daily Oral PrEP:
FTC/TAF vs FTC/TDF
 Not approved for PrEP
in cis-gender women
 Better bone and renal
safety profile
 More weight gain?
 $$
 Approved for PrEP in
cis-gender women
 Greater BMD loss,
more renal effects
 Less weight gain?
 $
TAF TDF

 International, randomized, double-blind phase IIb/III study
HIV-uninfected MSM and
TGW ≥ 18 yrs of age at high
risk of HIV infection*;
no HBV/HCV infection,
contraindication to gluteal
injection, seizures, or gluteal
tattoos/skin conditions
(N = 4566)
HPTN 083: Efficacy and Safety of LA Injectable CAB vs
Daily Oral TDF/FTC for PrEP in MSM and TGW
In Steps 1/2, all participants received matching placebo. At interim analysis on May 14, 2020 with 25%
of endpoints accrued, DSMB recommended termination of blinded study due to crossing of pre-
specified O’Brien-Fleming stopping bound.
*Any non-condom receptive anal intercourse, > 5 partners, stimulant drug use, incident rectal or
urethral STI (or incident syphilis) in past 6 mos; or SexPro Score ≤ 16 (US only).
†First 2 doses given 4 wks apart then every 8 wks thereafter.
CAB 30 mg PO QD
(n = 2282)
TDF/FTC PO QD
(n = 2284)
CAB LA 600 mg IM Q8W†
TDF/FTC PO QD
Wk 5
Step 1 Step 2
TDF/FTC PO QD
TDF/FTC PO QD
Step 3
Landovitz. AIDS 2020. Abstr OAXLB0101. NCT02720094.
Wk 153 Wk 201
 Primary endpoints: incident HIV infections in Steps 1/2, grade ≥ 2 AEs
 HPTN 084 ongoing: phase III companion study in cis gender women in Africa

0 9 17 25 33 41 49 57 65 73 81 89 97 105 113 121 129 137 145 153 161 169 177 185 193
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
TDF/FTC
CAB
Wks From Enrollment
1 yr 2 yrs 3 yrs
HR: 0.34 (95% CI: 0.18-0.62;
P = .0005)
HPTN 083: HIV Incidence (ITT) With LA Injectable CAB
vs Daily Oral TDF/FTC PrEP
Landovitz. AIDS 2020. Abstr OAXLB0101. Reproduced with permission. Slide credit: clinicaloptions.com

Median Weight Δ, kg/yr (95% CI) CAB TDF/FTC P Value
Wk 0-40 1.54 (1.00 to 2.00) -0.51 (-0.80 to -0.22) < .001
Wk 40-105 1.07 (0.61 to 1.5) 1.06 (0.79 to 1.3) .93
Overall 1.30 (0.99 to 1.60) 0.31 (-0.12 to -0.49) < .001
HPTN 083: Adverse Events and Weight Change
 2.2% (n = 47) of CAB recipients permanently discontinued CAB for injection-related
AE; risk of injection-related discontinuation strongly predicted by ISR severity
Landovitz. AIDS 2020. Abstr OAXLB0101. Slide credit: clinicaloptions.com
Grade ≥ 2 AE, % (n) CAB (n = 2282) TDF/FTC (n = 2284) P Value
Any 91.9 (2096) 92.3 (2106) --
CrCl rate decreased 68.5 (1562) 72.0 (1642) .01
Nasopharyngitis 19.3 (440) 17.0 (388) .04
Blood glucose increased 9.0 (206) 5.1 (117) < .001
Pyrexia* 5.4 (121) 2.6 (60) < .001
*Occurred within 7 days of injection: 70% in CAB arm vs 16% in TDF/FTC arm; event probability: 0.65% vs 0.05%, respectively.

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