Современное лечение ВИЧ: лечение многократно леченных пациентов с резистентностью /Contemporary Management of HIV: ART Management in Heavily Treatment–Experienced Patients.2020

Contemporary Management of HIV:
ART Management in Heavily Treatment–
Experienced Patients
This program is supported by an
educational grant from ViiV Healthcare.

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.

Outline
 Scope of the Problem
 Assessment of Virologic Failure
 Current Options for Active Drugs in Patients With Multiclass Resistance
 Case-Based Expert Guidance on Selecting the Next Line of Therapy

A Clinical Challenge: Heavily Treatment–Experienced
People With HIV
 ART with novel mechanisms of action plays a critical role for a small
proportion of people with HIV: those with resistance to multiple drug
classes and no/limited treatment options[1,2]
 2 primary target populations[3-5]
1) Older people with HIV treated in early days of ART with less potent regimens
that had low resistance barriers
2) Younger people with congenital HIV infection, now adults
 Currently, maraviroc, ibalizumab, fostemsavir, and enfuvirtide are the only
options[6-8]
‒ Fostemsavir administered orally, others injectable; some people already have
resistance to enfuvirtide
Slide credit: clinicaloptions.com
1. Struble. AIDS Lond Engl. 2005;19:747. 2. Richman. AIDS Lond Engl. 2004;18:1393. 3. Weinstock.
J Infect Dis. 2004;189:2174. 4. Yazdanpanah. Clin Infect Dis. 2009;49:1441. 5. Tassiopoulos. Clin Infect Dis.
2020;71:133. 6. Emu. NEJM. 2018;379:645. 7. Reeves. J Virol. 2005;79:4991. 8. Kozal. NEJM. 2020;382:1232.

Mid
’90s
Late
’00s
Early
’00s
Late
’90s
Early
’90s
Late
’80s
Early
’80s
No
ART
ZDV
mono-
therapy
Sequential NRTI
monotherapy and
dual-NRTI therapy
“Sequential
monotherapy”
with PIs/NNRTIs
Deferral
of
therapy
Highly adherent patients aggressively
treated with nonsuppressive regimens led
to selection of multidrug-resistant HIV
Who Are the People With Multidrug Resistant HIV?
Earlier
initiation of
therapy with
better
treatments
“Hit
hard, hit
early”

Prevalence of Heavily Treatment–Experienced Patients
With Multiclass Resistance/Limited Treatment Options
 CNICS cohort of > 26,000 ART-experienced people with HIV receiving care in the US
 Limited treatment options defined as ≤ 2 available classes with ≤ 2 active drugs per
class by resistance testing
Slide credit: clinicaloptions.comBajema. IAS 2019. Abstr MOPEB246.
18
16
14
12
10
8
6
4
2
0
PrevalenceofLimited
TreatmentOptions(%)
5.2%
2000
1.8%
1.0% 0.8%
Yr
7.5%
2002 2004 2006 2008 2010 2012 2014 2016

High Rates of Treatment Failure Among Patients With
Perinatally Acquired HIV
 Young adults with perinatally acquired HIV are currently transitioning to
adult care
 Pediatric HIV/AIDS AMP Up cohort: among 88 participants with available
viral load testing, 56% had ≥ 1 instance of unsuppressed viremia in yr prior
to transition
‒ Black participants were more likely to have unsuppressed HIV
N (%)
Total
(N = 88)
Unsuppressed HIV-1 RNA
(n = 49)
Suppressed HIV-1 RNA
(n = 39)
P Value
Male 25 (28) 11 (22) 14 (36)
.16
Female 63 (72) 38 (78) 25 (64)
Black 49 (58) 31 (69) 18 (46)
.04
White/other 35 (42) 14 (31) 21 (54)
Tassiopoulos. Clin Infect Dis. 2020;71:133.

Assessment of Virologic Failure

DHHS: Managing Virologic Failure
 “Assessing and managing a patient who is experiencing failure of
antiretroviral therapy (ART) is complex—expert advice is critical and
should be sought”
 Evaluation
‒ Adherence
‒ Drug–drug and drug–food interactions
‒ Drug tolerability
‒ HIV-1 RNA and CD4+ cell counts over time
‒ ART history
‒ Prior and current resistance test results
Slide credit: clinicaloptions.comDHHS ART Guidelines. December 2019.

Some With Refractory Treatment Failure Will Respond
to Their Current Regimen if Adherence Is Assured
 8-day, in-patient directly observed ART for patients with extensive ART resistance
and high rates of self-reported adherence (N = 20) (no regimen change)
‒ 9/20 had virologic response (> 0.5 log10 copies/mL decrease in HIV-1 RNA)
‒ 4/5 (80%) with perinatally acquired HIV had virologic response
Baseline Characteristic Total (N = 20) DOT Responders (n = 9) DOT Nonresponders (n = 11) P Value
Median age, yrs (IQR) 45.5 (26.0-51.3) 26.0 (24.0-47.0) 49.0 (42.5-51.5) .09
Post-HS education, n (%) 14 (70.0) 4 (44.4) 10 (90.9) .03
Median HIV-1 RNA, log10 copies/mL (IQR) 4.46 (4.32-5.00) 4.35 (4.17-4.51) 4.64 (4.36-5.00) .33
Median CD4+ cell count, cells/mm3 (IQR) 54.0 (13.8-90.3) 66.0 (26.0-89.0) 50.0 (10.5-82.0) .57
Mean time on ART, yrs (SE) 17.2 (6.1) 14.2 (6.1) 19.6 (5.2) .047
Mean number previous ART drugs (SE) 11.8 (4.5) 8.8 (3.7) 14.3 (3.6) .004
Median number major & minor DRMs (IQR) 14 (5.0-18.0) 5.0 (3.0-7.0) 18.0 (14.5-19.0) < .001
Median GSS (IQR) 1.0 (0.1-2.0) 2.0 (2.0-2.6) 0.1 (0.0-0.3) < .001
Winchester. Clin Infect Dis. 2020;70:1222.

DOT in Patients With Extensive ART Resistance:
Post-DOT Outcomes
Post DOT Outcomes for Participants
With ≥ 6-Mos Follow-up, n/N (%)
Total
DOT
Responders
DOT
Nonresponders
P Value
HIV-1 RNA < 40 copies/mL at
≥ 1 study time point
11/17 (64.7) 5/6 (83.3) 6/10 (60.0)* .42
HIV-1 RNA < 40 copies/mL
maintained for 6 mos
5/17 (29.4) 1/6 (16.7) 3/10 (30.0) > .99
CD4+ cell count increase from
screening to 6 mos
13/16 (81.3) 6/6 (100.0) 7/10 (70.0) .16
*8 patients switched to optimized ART regimens after first dose; results reflect new regimen.
Winchester. Clin Infect Dis. 2020;70:1222.

Prior Failed Strategies for Management of Patients With
Multidrug Resistant HIV
 “MEGA-HAART”: using 6 or more drugs in untested combinations[1]
 “Double-boosted PIs”: 2 protease inhibitors with ritonavir[2]
 Hydroxyurea ± mycophenolate: raised intracellular concentrations of
didanosine and abacavir[3]
 Treatment interruptions: regrowth of wild-type virus to “resensitize” it
to available therapies[4]
1. Miller. Antivir Ther. 2000;5:49. 2. Chetchotisakd. HIV Med. 2007;8:529.
3. Hellinger. J Infect Dis. 2000;181:540. 4. Lawrence. NEJM. 2003;349:837

DHHS: Selection of New Regimen
 Perform drug resistance testing while patient is receiving the failing
regimen
‒ If this timing not possible, test within 4 wks of therapy discontinuation
 New regimen should include 2 (and preferably 3) fully active agents
 Definition of “fully active agent”: uncompromised activity expected per
patient’s treatment history and results of resistance testing
‒ May have a novel mechanism of action

DHHS: Drug Resistance Testing in Virologic Failure
 Drug resistance is cumulative, so evaluation of drug resistance must
consider previous ART history and all previous genotypic or
phenotypic resistance test results
 Archived drug resistance mutations may not be detected by standard
drug resistance tests, particularly if tests performed when patient is
not taking drug in question
‒ Drug-resistant viruses that constitute < 10% to 20% of circulating virus
population likely not detected by commercially available assays
 Do not discontinue or briefly interrupt therapy in patients with overt
or low-level viremia because of risk of rapid HIV-1 RNA increase, CD4+
cell count decrease, and clinical progression

DHHS: Types of Drug Resistance Testing
 Genotypic testing preferred over phenotypic resistance testing for
virologic failure/suboptimal response with first-line or second-line ART,
if resistance mutation patterns known or not expected to be complex
 Addition of phenotypic testing to genotypic resistance testing
recommended for persons with known or suspected complex drug
resistance mutation patterns
 Genotypic sequencing assay that analyzes HIV-1 proviral DNA may
provide additional information on drug resistance in patients with low
plasma HIV-1 RNA levels
‒ However, these assays might still miss some or all previous drug
resistance mutations and thus should be interpreted with caution

100
Third-line Treatment: Targeted Resistance Testing Helps
Select Active Regimen in Resource-Limited Settings
 Regimens with ≥ 2 active drugs effective for third-line ART
Grinsztejn. Lancet HIV. 2019;6:PE588. Slide credit: clinicaloptions.com
B1 B2 B3 C D
HIV-1RNA≤200c/mL(%)
A
80
60
40
20
0
44
88 88
74
90
100
N = 287 74 72 8 70 34
 No LPV/RTV
resistance
 Susceptible to
≥ 1 NRTI
 Continue
second-line ART
 Best available
NRTIs + DRV/r +
RAL
 DRV/r + RAL +
ETR
 HBsAg+
 DRV/r + RAL +
(FTC or 3TC)/
TDF
 LPV/RTV & ETR
resistant
 DRV susceptible
 No prior RAL
 DRV/r + RAL +
(FTC or 3TC)/
TDF
 Not eligible for
A, B, or C
 Best available
NRTIs + DRV/r +
RAL
LPV/RTV resistant; no prior RAL; DRV & ETR susceptible

Current Options for Active Drugs
in Patients With Multiclass Resistance

Current Options for Active Drugs in Patients with
Multiclass Resistance
 Use of new drugs with a novel
mechanism of action and no
cross-resistance
‒ Ibalizumab
‒ Fostemsavir
‒ Enfuvirtide: if no prior history of
ENF failure
‒ Maraviroc: if R5-only virus
confirmed (less common in highly
treatment-experienced patients)
 Use of drugs in existing drug
classes that may have residual
activity
‒ NRTI: emtricitabine, lamivudine
‒ NNRTI: doravirine, etravirine
‒ PI: darunavir
‒ INSTI: dolutegravir
Slide credit: clinicaloptions.comDHHS ART Guidelines. December 2019. FostemsavirPI.

Monoclonal Antibody Ibalizumab Approved by FDA on
March 6, 2018
 Ibalizumab binds to the T-cell CD4 receptor and prevents
conformational changes in CD4-gp120 complex, thereby blocking viral
entry[1]
 FDA approved in combination with other ARVs for heavily treatment–
experienced adults with multidrug-resistant HIV infection who are
experiencing failure of current regimen[2]
‒ May be used for patients without sufficient treatment options
Slide credit: clinicaloptions.com1. Emu. NEJM. 2018;379:645. 2. Ibalizumab-uiykPI.

TMB-301: Ibalizumab in Pretreated Patients Infected
With Multidrug-Resistant HIV
 Single-arm, open-label phase III trial in patients with virologic failure
‒ Primary endpoint: HIV-1 RNA decrease ≥ 0.5 log10 copies/mL from baseline to
Day 14
 53% with resistance to all drugs from ≥ 3 classes; 68% with INSTI resistance
 Mean BL VL 4.5 log10 copies/mL; mean BL CD4+ cell count: 150 cells/mm³
Emu. NEJM. 2018;379:645.
Patients with HIV-1 RNA
> 1000 copies/mL;
on ART ≥ 6 mos, on stable ART
≥ 8 wks; resistant to ≥ 1 ARV
from 3 classes, sensitive to
≥ 1 ARV for OBR
(N = 40)
Wk 25
Ibalizumab
2000 mg IV Day 7
(loading dose)
Continue failing ART
Days 0-14
Ibalizumab
800 mg IV Day 21, Q2W
(maintenance dose)
Switch to OBR
Day 14
Day 14
Primary Endpoint
Control Period:
Day 0-7
Patients who
completed Wk 24 could
continue for an
additional 24 wks

TMB-301/-311: Virologic Outcomes Through 96 Wks
 TMB-311: patients enrolled in US and Puerto Rico who completed 25
wks in TMB-301 continued ibalizumab 800 mg Q2W for up to 96 wks
*Primary endpoint; P < .0001 vs 3% at end of control period. †3 patients without ≥ 0.5 log10 HIV-1 RNA decrease at Day 14 later reached
HIV-1 RNA < 50 copies/mL with ibalizumab + OBR.[5]
1. Emu. NEJM. 2018;379:645. 2. Emu. IDSA 2017. Abstr 1686. 3. Emu. HIV Glasgow 2018. Abstr O345.
4. Emu. CROI 2019. Abstr 485. 5. DeJesus.HIV Glasgow 2018. Abstr P064.
Virologic Outcome
Day 14[1]
(N = 40)
Wk 25[1]
(N = 40)
Wk 48[2,3]
(N = 27)
Wk 96[4]
(N = 27)
≥ 0.5 log10 HIV-1 RNA decrease, % 83*† 63 NR NR
≥ 1.0 log10 HIV-1 RNA decrease, % 60 55 67 NR
Mean log10 HIV-1 RNA decrease 1.1 1.6 2.1 NR
Median log10 HIV-1 RNA decrease NR 2.5 2.8 2.8
HIV-1 RNA < 50 copies/mL, % NR 43 59 56
HIV-1 RNA < 200 copies/mL, % NR 50 63 NR

TMB-301/-311: Safety and Immunologic Outcomes
Through 96 Wks
 No new safety signals emerged from
Wk 25 to Wk 96[2]
‒ 22 out of 27 patients completed
treatment to 96 wks
‒ Reasons for early d/c (none related to
ibalizumab): Consent withdrawal: n = 2;
physician decision: n = 1; death: n = 2
(advanced CVD, CMV progression)
 Median CD4+ cell count increases from
baseline[2]:
‒ Wk 25: 42 cells/mm3 (n = 27)
‒ Wk 96: 45 cells/mm3 (n = 22)
1. Emu. NEJM. 2018;379:645. 2. Emu. CROI 2019. Abstr 485.
AEs Through Wk 25,[1] n (%) Patients (N = 40)
Any AE 32 (80)
Assessed as related to ibalizumab 7 (18)
Leading to d/c of ibalizumab 5 (13)
Occurring in patients who died 4 (10)
Serious AE 9 (23)
AEs occurring in > 10% of patients
 Diarrhea 8 (20)
 Dizziness 5 (13)
 Fatigue 5 (13)
 Nausea 5 (13)
 Pyrexia 5 (13)
 Rash 5 (13)

Ibalizumab: Key Take-aways
 March 2018: FDA approved as IV infusion for heavily treatment–experienced adults
with multidrug-resistant HIV infection and virologic failure[1]
 Recommendations from guidelines
‒ DHHS: “Patients with ongoing detectable viremia who lack sufficient treatment
options to construct a fully suppressive regimen may be candidates for the recently
approved CD4 postattachment inhibitor ibalizumab”[2]
‒ IAS-USA: “Ibalizumab . . . can be used when creating a salvage regimen for individuals
with extremely limited treatment options.”[3]
 Needs to be combined with other active agents to achieve viral suppression
 Take advantage of the IV infusion every 2 wks to intensify adherence to other
components of the regimen
1. Ibalizumab-uiyk PI. 2. DHHS ART Guidelines. December 2019. 3. Saag. JAMA. 2020;[Epub]. Slide credit: clinicaloptions.com

Attachment Inhibitor Fostemsavir Approved by FDA on
July 2, 2020
 Temsavir—active metabolite of fostemsavir—binds to HIV-1 envelope
glycoprotein 120 and prevents conformational changes needed for viral
interaction with CD4, thereby blocking viral attachment and
subsequent entry[1]
 FDA approved in combination with other ARVs for heavily treatment–
experienced adults with multidrug-resistant HIV infection who are
experiencing failure of current regimen[2]
‒ Failure may be due to resistance, intolerance, or safety considerations
 IAS-USA: “…fostemsavir can be used when creating a salvage regimen
for individuals with extremely limited treatment options.”[3]
Slide credit: clinicaloptions.com1. Kozal. NEJM. 2020;382:1232. 2. Fostemsavir PI. 3. Saag. JAMA. 2020;[Epub].

BRIGHTE: Fostemsavir in Heavily Treatment–
Experienced Adults With Multidrug-Resistant HIV
Randomized Cohort
1-2 remaining ARV classes
(≥ 1 fully active* approved agent/class),
cannot construct viable regimen with
remaining agents
(n = 272)
*No evidence of resistance; patient eligible for, tolerant of, willing to receive the ARV.
Primary Endpoint
Mean Δ in HIV-1 RNA,
log10 c/mL (95% CI)
-0.79 (-0.88 to -0.70)
-0.17 (-0.33 to -0.01)
Day 9
FTR 600 mg BID +
Failing Regimen
(n = 203)
Placebo +
Failing Regimen
(n = 69)
FTR 600 mg BID + OBT
FTR 600 mg BID + OBT
Treatment ∆: -0.63
Nonrandomized Cohort
No remaining ARV classes and no
fully active* approved agents
(n = 99)
FTR 600 mg BID + OBT (investigational agents allowed)
Day 1
Kozal. NEJM. 2020;382:1232. Pialoux. AIDS 2018. Abstr THPEB045.
Day 8 Wk 96

BRIGHTE: Virologic and Safety Outcomes
Through 96 Wks
Outcome at Wk 96, n (%)
Randomized
(n = 272)
Nonrandomized
(n = 99)
HIV-1 RNA < 40 c/mL 163 (60) 37 (37)
HIV-1 RNA ≥ 40 c/mL 81 (30) 43 (43)
No virologic data
 D/c due to AE or death
28 (10)
15 (6)
19 (19)
14 (14)
*Snapshot analysis excluded BL data; 1 patient had BL HIV-1 RNA < 40 c/mL.
Lataillade. IAS 2019. Abstr MOAB0102.
Randomized Cohort (n = 272) Nonrandomized Cohort (n = 99)
SnapshotAnalysis:
HIV-1RNA<40c/mL(%)
100
80
60
40
20
0
BL* Wk 24 Wk 48 Wk 72 Wk 96
53 54 53
60
100
80
60
40
20
0
BL* Wk 24 Wk 48 Wk 72 Wk 96
37 38 35 37
 Cumulative safety outcomes
through Wk 96 for all
treated patients
‒ Drug-related AEs: grade 2-4,
21%; serious, 3%
‒ AEs leading to d/c: 7%
‒ Death: 8%; most due to AIDS-
related events or acute
infections, 1 deemed
treatment-related (IRIS)

BRIGHTE: CD4+ Cell Counts Through Wk 96
 Among randomized patients with BL CD4+ cell count < 50 cells/mm3,
56% had a CD4+ cell count ≥ 200 cells/mm3 at Wk 96
90
(n = 247)
41
(n = 87)
64
(n = 83)
96
(n = 72)
139
(n = 228)
172
(n = 217)
205
(n = 213)
119
(n = 65)
Randomized cohort (n = 272)
Nonrandomized cohort (n = 99)
*BL mean CD4+ cell count, cells/mm3: randomized cohort, 153; nonrandomized cohort, 99.
BL CD4+ Cell Counts (cells/mm3)
+240
By Cohort By BL CD4+ Cell Count (Randomized Cohort)
+201
+172
+199
+205
MeanChangeFromBLin
CD4+CellCount(cells/mm3)±SD
450
400
350
300
250
50
200
150
100
0
BL* Wk 24 Wk 48 Wk 72 Wk 96
MeanChangeFromBLin
CD4+CellCounts(cells/mm3)
450
400
350
300
250
50
200
150
100
0
BL Wk 24 Wk 48 Wk 72 Wk 96
< 20 (n = 72)
20 to < 50 (n = 25)
50 to < 100 (n = 39)
100 to < 200 (n = 63)
≥ 200 (n = 73)
Lataillade. IAS 2019. Abstr MOAB0102.

Fostemsavir: Key Take-aways
 July 2020: FDA approved as twice daily oral tablet for heavily
treatment–experienced adults with multidrug-resistant HIV infection
and regimen failure[1]
 DHHS ART guidelines not yet updated to reflect FDA approval of
fostemsavir[2]
 Needs to be combined with other active agents to achieve viral
suppression
1. Fostemsavir PI. 2. DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com

Current Options for Active Drugs in Patients With
Multiclass Resistance
 Use of new drugs with a novel
mechanism of action and no
cross-resistance
‒ Ibalizumab
‒ Fostemsavir
‒ Enfuvirtide: if no prior history of
ENF failure
‒ Maraviroc: if R5-only virus
confirmed (less common in highly
treatment-experienced patients)
 Use of drugs in existing drug
classes that may have residual
activity
‒ NRTI: emtricitabine, lamivudine
‒ NNRTI: doravirine, etravirine
‒ PI: darunavir
‒ INSTI: dolutegravir
DHHS ART Guidelines. December 2019. FostemsavirPI. Slide credit: clinicaloptions.com

NRTIs Maintain Activity Even With Extensive Resistance
 Second-line therapy after failure of 2 NRTIs plus NNRTI-based regimen (N = 1277)
 Recycled “inactive” NRTIs plus boosted PI more active than PI monotherapy
Paton. Lancet HIV. 2017;4:PE341.
Wk
100
80
60
40
0
20
HIV-1RNA<400copies/mL(%)
1440 4 12 24 36 48 64 80 96 112 128
PI plus 0 active NRTIs (n > 188)
PI plus 2-3 active NRTIs (n > 23)
PI monotherapy (n > 374)
PI plus 1 active NRTI (n > 104)
PI plus raltegravir (n > 351)

Patients(%)
Baseline INSTI Mutations
n = 183 126 36 21
69
24
79
58
Overall No Q148 Q148 + 1* Q148 + ≥ 2*
100
80
60
40
20
0
*Key secondary mutations were G140A/C/S, L74I and E138A/K/T.
VIKING-3: DTG BID in Previously Treated Patients With
RAL and EVG Resistance
HIV-1 RNA < 50 c/mL at Wks 24 and 48 (ITT-E)
63
183 126
71
36
56
21
29
Wk 24 DTG 50 mg BID + OBR
Wk 48 DTG 50 mg BID + OBR
Castagna. J Infect Dis. 2014;210:354. Vavro. EUDRW 2014. Abstr O_10. Slide credit: clinicaloptions.com
 4 of 33 patients with N155H
mutation at baseline had
protocol-defined virologic
failure

Use of Darunavir in Patients With PI Resistance
 For most patients with PI resistance, the PI of choice is darunavir
‒ No DRV-associated mutations: DRV once daily
‒ Any DRV-associated mutations: DRV twice daily
 Exception: some rare DRV-resistant viruses retain susceptibility to
tipranavir
‒ Caution: avoid use of tipranavir with dolutegravir and INSTI resistance
Darunavir PI. Dolutegravir PI. DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com
V V L I I I T L I L
11 32 33 47 50 54 74 76 84 89
I I F V V M
L
P V V V

Doravirine
In vitro
resistance
profile shows
DOR is active
against major
variants
selected by
EFV and RPV
Mutations
Selected by DOR
(V106A, F227L,
L234I, V108I)
Mutations
Selected by EFV
Mutations
Selected by RPV
Feng. Antimicrob Agents Chemother. 2015;59:590.
0
20
40
60
80
100
Fold-change
RPV
EFV
DOR
0
20
40
60
80
100
Fold-change
DOR
RPV
EFV
0
20
40
60
80
100
Fold-change
DOR
EFV
RPV
0
20
40
60
80
100
DOR
EFV
RPV
0
20
40
60
80
100
DOR
RPV
EFV
0
20
40
60
80
100
RPV
EFV
DOR
0
20
40
60
80
100
DOR
RPV
EFV
0
20
40
60
80
100
DOR
EFV
RPV

Summary
 Target population of patients with multidrug-resistant HIV and few
treatment options is small but in high need
 Among currently approved drugs, ibalizumab, fostemsavir, and
enfuvirtide are the only agents with no cross resistance with NRTIs,
NNRTIs, PIs, and INSTIs
‒ Some patients may have already received enfuvirtide and have resistance
 Background regimens can be constructed using drugs with residual
activity despite prior failure with resistance

Expert Guidance
on Selecting the Next Line of Therapy: Case 1

Patient Case 1:
History and Current Presentation
 49-yr-old man with a long treatment
history (next slide)
‒ Currently on a complex regimen
following previous virologic suppression
for > 3 yrs
 Methamphetamine relapse in 2016 with
binges and periods of loss to follow-up
‒ Highly variable HIV-1 RNA (< 40 to
10,000 copies/mL)
‒ Chaotic visits prevented adequate
resistance testing
 Recently regained stable housing and
family support
 Now returns to clinic, presents with
oral thrush and weight loss
 Unable to swallow ETR for some time
but has resumed adherence to
other meds
Parameter at Current Presentation Value
CD4+ cell count, cells/mm3 38
HIV-1 RNA, copies/mL 32,500
Current ART doses
 DRV/RTV, mg BID
 ETR, mg BID
 RAL, mg BID
 FTC/TDF, mg QD
600/100
200
400
200/300

Past Regimen Start Date Stop Date
AZT Jan 1995 May 1996
AZT + 3TC May 1996 July 1996
IDV + 3TC + d4T July 1996 June 1997
NFV + NVP + 3TC June 1997 July 1997
SQV + NFV + 3TC July 1997 Aug 1997
SQV + NFV + DLV Aug 1997 Dec 1997
EFV + APV + ABC Feb 1998 July 1998
NFV + ddI July 1998 Sept 1998
NFV + NVP + AZT + 3TC Sept 1998 Nov 2000
APV + RTVb + d4T +3TC Nov 2000 Aug 2001
LPV/RTV + IDV + 3TC + TDF Aug 2001 Aug 2001
IDV + 3TC + TDF Aug 2001 Aug 2001
IDV + RTVb + ddI + 3TC + TDF Aug 2001 Sept 2001
ENF + LPV/RTV + 3TC + TDF Jan 2002 Apr 2002
ENF + 3TC + TDF Apr 2002 May 2002
Patient Case 1: ART History
STD = study medication T1249
Past Regimen Start Date Stop Date
ENF + LPV/RTV + 3TC + TDF May 2002 Nov 2003
ENF + ATV + RTVb + 3TC + TDF Nov 2003 Mar 2004
ENF + RTV + 3TC + TDF Mar 2004 Apr 2004
ENF + 3TC + TDF Apr 2004 May 2005
ENF + TPV + RTVb + 3TC + TDF May 2005 Dec 2005
ENF + 3TC + TDF Dec 2005 Dec 2005
ENF + TPV + RTVb + 3TC + TDF Dec 2005 Aug 2006
ENF + AZT + DRV + RTVb + 3TC + TDF Aug 2006 July 2007
ENF + AZT + DRV + RTVb + 3TC + TDF Aug 2007 Mar 2008
RAL + ENF + AZT + DRV + RTVb + 3TC + TDF Mar 2008 Aug 2008
RAL + AZT + DRV + RTVb + 3TC + TDF Aug 2008 Sept 2009
RAL + ENF + AZT + DRV + RTVb + 3TC + TDF Sept 2009 Jan 2010
RAL + AZT + DRV + RTVb + 3TC + TDF Jan 2010 Dec 2010
AZT + DRV + RTVb + 3TC + TDF Dec 2010 Jan 2012
AZT + DRV + RTVb + 3TC + TDF + T1249* Jan 2012 Jan 2012
*Study drug

Case 1: RT Resistance Testing Results
Drug
Susceptibility Testing
Stanford University HIV Drug Resistance Database
Pheno/Geno Seq Net Assessment
NRTI (mutations*: M41L, E44A, V75M, F77L, V118V/I, M184V, L210W, T215Y)
 ABC
 ddI
 FTC
 3TC
 d4T
 AZT
 TDF
P/N
N/N
N/N
N/N
N/N
N/N
P/N
Resistant
Resistant
Resistant
Resistant
Resistant
Resistant
Partial
High-level resistance
Intermediate resistance
NNRTI (mutations*: K103S, K103N, G190A)
 DLV
 EFV
 ETR
 NVP
 DOR
 RPV
Y/N
Y/N
Y/Y
N/N
NA
NA
Sensitive
Sensitive
Sensitive
Resistant
NA
NA
NA
Potential low-level resistance
Susceptible
Low-level resistance
*Additional mutations: V118I.
https://hivdb.stanford.edu/ Slide credit: clinicaloptions.com

Case 1: PI Resistance Testing Results
 6 darunavir resistance mutations
PI (Mutations: L10V, V11I, I13V, V32I,
L33F, E35D, M36I, M46I, I54L, I62V,
A71V, T74P, V82T, I84V)
Susceptibility Testing
Stanford University HIV
Drug Resistance DatabasePheno/Geno Seq Net Assessment
ATV/RTV*
DRV/RTV
FPV/RTV*
IDV/RTV
LPV/RTV
NFV
RTV
SQV/RTV*
TPV/RTV
N/N
N/N
N/N
N/N
N/N†
N/N
N/N
N/N
N/N
Resistant
Resistant
Resistant
Resistant
Resistant†
Resistant
Resistant
Resistant
Resistant
NA
*Similar susceptibility testing results for unboosted drug. †Susceptibility testing results for unboosted LPV.

Case 1: Cumulative Resistance From Previous Test
Results
 10F, 10I, 10V, 11I, 13V, 20R, 24I, 32I, 33F, 35D, 36I, 41K, 46I, 54V, 54L,
62V, 63P, 66V, 71V, 74P, 82T, 82A, 84V, 89V, 93L
 35I, 41L, 43E, 44A, 68G, 74V, 74I, 75M, 77L, 103N, 103S, 118I, 118V,
135T, 179I, 184V, 190A, 210W, 215Y, 371V, 399D
 RT/PRO replication capacity: 16%
Six darunavir resistance mutations

Case 1: Enfuvirtide and Tropism Results
Drug Susceptibility Summary
Enfuvirtide
 Reduced susceptibility
 22-fold increase in IC50
Maraviroc
 CCR5-tropic virus; CCR5 antagonist anticipated to be
active

Case 1: INSTI Resistance Results
 G140S and Q148H  full resistance to RAL and EVG; 4.75-fold
reduction in susceptibility to DTG
 INSTI replication capacity: 166%
INSTI (Mutations:
G140S and Q148H)
Susceptibility Testing Stanford University HIV Drug Resistance
DatabasePheno/Geno Seq Net Assessment
 DTG
 EVG
 RAL
 BIC
P/P
N/N
N/N
NA
Partial
Resistant
Resistant
NA

Potential Regimen Options for this Patient
INSTI plus additional oral active agent, plus additional IV agent(s)
 DTG BID + (MVC and/or DOR) + NRTI
 DTG BID + (MVC and/or DOR) + ibalizumab and/or fostemsavir
 DTG BID + (MVC and/or DOR) + ibalizumab and/or fostemsavir + NRTI
 With or without DRV/RTV?

VIKING: DTG Activity in Patients With RAL Resistance
 Patients with VF on RAL-based regimen continued background regimen and
added DTG through Day 10 followed by background regimen optimization
HIV-1 RNA Level Change After DTG Addition According to FC in DTG IC50 vs WT
HIV-1RNAChangeFromBaselineto
Day11(log10copies/mL)
Baseline DTG IC50 Fold-Change vs WT Virus
Eron. J Infect Dis. 2013;207:740. Soriano. EACS 2011. Abstr. PS1/2. Slide credit: clinicaloptions.com
Q148 + 1
Q148 + 2
Mixture
N155
Y143
Other IN mutations
DTG 50 mg QD
DTG 50 mg BID
0.5 1 2 4 8 16 32
0.5 1 2 4 8 16 32
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0

TMB-301/-311: Virologic Response by DRV Resistance
 Single-arm, phase III trial of ibalizumab + OBR in treatment-experienced patients with virologic
failure and multidrug resistance
 27 patients with DRV resistance: 20 had major DRV resistance mutations (V32/I47/I150/I154/L76)
 18 of 27 included DRV/r in OBR, 15 had daily dose > 600 mg; 5/9 who discontinued early were in
DRV resistance group
Emu. CROI 2019. Abstr 485. Slide credit: clinicaloptions.com
Virologic Outcome, % (n/N)
DRV Resistant DRV Susceptible
No DRV in
OBR
DRV in OBR
No DRV in
OBR
DRV in OBR
Median OSS 2.0 1.0 2.0 2.5
> 0.5 log10 HIV-1 RNA decrease by Day 14 78 (7/9) 83 (15/18) 80 (4/5) 88 (7/8)
> 0.5 log10 HIV-1 RNA decrease by Wk 25 78 (7/9) 61 (11/18) 60 (3/5) 63 (5/8)
HIV-1 RNA < 50 copies/mL at Wk 25 78 (7/9) 28 (5/18) 40 (2/5) 38 (3/8)

OPTIONS: Omitting vs Adding NRTI for Treatment-
Experienced Patients Experiencing PI-Based ART Failure
Gandhi et al JID 2019Gandhi. J Infect Dis. 2020;221:1407. Slide credit: clinicaloptions.com
Risk for Confirmed Virologic Failure
ProbabilityofNotHaving
VirologicFailure
Wk
Omit NRTI group
Add NRTI group
Highly resistant group (add
NRTI)
Patients at Risk, n
Omit NRTI group
Add NRTI group
Highly resistant group
(add NRTI)
179
181
53
169
171
48
149
149
37
141
138
33
132
135
31
128
128
28
125
123
26
121
118
24
119
113
22
1.0
0.8
0.5
0.4
0.2
0
0 12 24 36 48 60 72 84 96

Expert Guidance
on Selecting the Next Line of Therapy: Case 2

Patient Case 2: Background
 28-yr-old woman, likely acquired infection
during perinatal/breast-feeding period
‒ Her mother emigrated from Guatemala
when she was 2 yrs old
‒ Both were diagnosed with HIV when her
mother presented with cryptococcal
meningitis
 Records are limited, but she was treated
with single and dual NRTI regimens with
incomplete viral suppression
 Started on 2 NRTIs + liquid RTV at ~ 8 yrs
of age with adherence difficulty and
progression of NRTI resistance
‒ CD4+ cell count remained ~ 500 cells/mm3
 Partial viral suppression maintained since
17 yrs of age on INSTI (RAL→ DTG) +
NNRTI (ETR → RPV) + 2 NRTIs
‒ Currently receiving DTG + RPV/FTC/TAF
 Attempted PI use several times (most
recently DRV/COBI) with very poor
tolerance; mostly nausea/vomiting and
inability to swallow pills
 Recent HIV-1 RNA results have ranged
from 10,000 to 15,000 copies/mL
 CD4+ cell count has been declining and
was most recently 180 cells/mm3

Antiretrovirals Available by Pediatric Age Group in 2012
52
http://www.pipelinereport.org/TOC/pediatric-ARV
Slide credit: clinicaloptions.comhttp://www.pipelinereport.org/TOC/pediatric-ARV
Fosamprenavir
Stavudine
Nevirapine
Ritonavir
Lopinavir
Zidovudine
Abacavir
Lamivudine
Emtricitabine
Didanosine
Age 0-2 Yrs
Raltegravir
Efavirenz
Tenofovir DF
Darunavir
Tipranavir
Nelfinavir
Age 2-6 Yrs
List for 0-2 yrs +
Enfuvirtide
Etravirine
Lists for 0-6 yrs +
Age 6-12 Yrs
Maraviroc (> 16)
Delavidine (> 16)
Lists for 0-12 yrs +
Age 12-18 Yrs

Patient Case 2: Background
 HBV and HAV immune; HCV negative
 Weight: 48 kg with lipoatrophy
 Recurrent vaginal candidiasis but has never had opportunistic infection
 Most recent genotyping results:
‒ RT: 41L, 69insert, 184V, 215Y, 101P, 106I, 181C, 179F
‒ PI: 20T, 82A, 90M
‒ INSTI: 92Q, 140S, Q148Q/R
‒ Tropism: CXCR4 variant
 Naive to ENF, DOR, BIC, and TPV Slide credit: clinicaloptions.com

Case 2: Stanford Database Resistance Interpretation
Drug
Stanford University HIV Drug
Resistance Database
NRTI (mutations: M41L, T69insertion, M184V, T215Y)
 ABC
 AZT
 FTC
 3TC
 TDF
NNRTI (mutations: K101P, V106I, V179F, Y181C)
 DOR
 EFV
 ETR
 NVP
 RPV
Drug
Stanford University HIV Drug
Resistance Database
PI (mutations: V82A, L90M, K20T)
 ATV/RTV
 DRV/RTV
 LPV/RTV
Susceptible
INSTI (mutations: E92Q, G140S, Q148R)
 BIC
 DTG
 EVG
 RAL
https://hivdb.stanford.edu/

Современное лечение ВИЧ: лечение многократно леченных пациентов с резистентностью /Contemporary Management of HIV: ART Management in Heavily Treatment–Experienced Patients.2020

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