Incorporating New ART Options Into First-line and Switch Strategies for HIV Care.2020

Incorporating New ART Options Into First-line and
Switch Strategies for HIV Care
Supported by an educational grant from
ViiV Healthcare

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Program Director
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

Faculty
José R. Arribas, MD
Research Director (HIV and Infectious
Diseases)
Hospital La Paz. IdiPAZ.
Madrid, Spain
Alexandra Calmy, MD, FMH, PhD
HIV/AIDS Unit Director
Infectious Diseases Division
Geneva University Hospitals
University of Geneva
Geneva, Switzerland
Laura Waters, MD
Consultant Physician, HIV/GU
Medicine
Mortimer Market Centre
CNWL NHS Trust
London, United Kingdom

Faculty Disclosures
José R. Arribas, MD, has disclosed that he has received consulting fees from
Aelix, Gilead Sciences, Janssen, Merck, Teva, and ViiV Healthcare and funds for
research support from Gilead Sciences, Merck, and ViiV Healthcare.
Alexandra Calmy, MD, FMH, PhD, has disclosed that she has received fees for
non-CME/CE services from Gilead Sciences.
Jean-Michel Molina, MD, PhD, has disclosed that he has received funds for
research support from Gilead Sciences; consulting fees from Gilead Sciences,
Merck, and ViiV Healthcare; and fees for non-CME/CE services from Janssen.
Laura Waters, MD, has disclosed that she has received consulting fees from
Cipla, Gilead Sciences, Janssen, Merck, Mylan, and ViiV Healthcare.

Reviewing Recent Advances in ART

Evolution of ART: 1987-1997
1997: 3-Drug Therapy[4]
1994: 2-NRTI Therapy[2,3]
1987: NRTI Monotherapy[1,2]
HIV-1RNAΔ(loglog10copies/mL)
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
24-Wk Response
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
24-Wk Response
0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
24-Wk Response
1. Fischl. NEJM. 1987;317:185. 2. Harrigan. J Acquir Immune Defic Syndr Hum Retrovirol. 1995;10 Suppl 1:S34.
3. Eron. NEJM. 1995;333:1662. 4. Gulick. NEJM. 1997;337:734.
Viral load trend inferred from
CD4 response.

US Mortality Among Persons 25-44 Yrs of Age, 1987-2016
Introduction of 3-Drug Therapy
Yr of Death
Deathsper100,000Population
1987
1989
1991
1995
1997
1999
2001
2003
2005
2007
2009
2011
2013
1993
2015
40
35
30
25
20
15
10
5
0
Unintentional injury
Cancer
Heart disease
Suicide
Homicide
HIV infection
https://www.cdc.gov/hiv/library/slideSets/.

Early 2-Drug vs 3-Drug Comparisons: Unboosted PI Era
 First-line*  Maintenance[5]
1. Hammer. NEJM. 1997;337:725. 2. Gulick. NEJM. 1997;337:734. 3. Montaner. JAMA. 1998;279:930.
4. Collier. NEJM. 1996;334:1011. 5. Rutherford. Cochrane Database Syst Rev. 2003:CD002037. Slide credit: clinicaloptions.com
‒ 2 NRTIs[1-4]
‒ NRTI + NNRTI[3]
‒ NRTI + PI[4]
‒ All inferior to 2 NRTIs + NNRTI
or PI
‒ 2 NRTIs
‒ NRTI + PI
‒ 2 PIs
‒ All inferior to continued
3-4 drugs
*Some patients had previously received ZDV.

‒ PI/b + CCR5[10]‒ PI/b + CCR5,[5]
PI + INSTI[6]
‒ PI/b + NRTI[7-9]‒ PI/b + NNRTI,[1]
NRTI,[2]
INSTI[3,4]
‒ Some low CD4+ cell count, high
HIV-1 RNA caveats (eg, with
DRV/RTV + RAL in NEAT001)[4]
Early 2-Drug vs 3-Drug Comparisons: Boosted PI Era
 Maintenance First-line
1. Riddler. NEJM. 2008;358:2095. 2. Figueroa. CROI 2018. Abstr 489. 3. Reynes. HIV Clin Trials. 2011;12:255. 4. Raffi. Lancet. 2014;384:1942.
5. Stellbrink. AIDS. 2016;30:1229. 6. Kozal. HIV Clin Trials. 2012;13:119. 7. Di Giambenedetto. J Antimicrob Chemother. 2017;72:1163.
8. Pulido. Clin Infect Dis. 2017;65:2112. 9. Perez-Molina. J Antimicrob Chemother. 2017;72:246. 10. Pett. Clin Infect Dis. 2016;63:122. Slide credit: clinicaloptions.com

Recommended
INSTI + 2 NRTIs (logPreferred)
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + FTC/TAF or XTC/TDF
 RAL + FTC/TAF or XTC/TDF
INSTI + 1 NRTI
 DTG + 3TC
NNRTI + 2 NRTIs
 DOR + FTC/(TAF or TDF), DOR/3TC/TDF
 RPV + 3TC/TDF, RPV/FTC/(TAF or TDF)
Boosted PI + 2 NRTIs
 DRV/COBI/FTC/TAF, DRV/COBI + XTC/TDF
 DRV + RTV + FTC/TAF or XTC/TDF
EACS Guidelines for First-line Therapy
Slide credit: clinicaloptions.comEACS Guidelines. November 2019.
Alternative
INSTI + 2 NRTIs
 EVG/COBI/FTC/(TAF or TDF)
 RAL + ABC/3TC
NNRTI + 2 NRTIs
 EFV + ABC/3TC, FTC/TAF, or 3TC/TDF
 EFV/FTC/TDF
Boosted PI + 2 NRTIs
 ATV/(COBI or RTV) + ABC/3TC, FTC/TAF, or
XTC/TDF
 (DRV/COBI or DRV + RTV) + ABC/3TC
Other
 (DRV/COBI or DRV + RTV) + RAL 400 mg BID

DHHS Guidelines for First-line Therapy
Slide credit: clinicaloptions.comDHHS Guidelines. December 2019.
Recommended for Most People With HIV
INSTI + 2 NRTIs
 BIC/FTC/TAF
 DTG/ABC/3TC
 DTG + XTC + (TAF or TDF)
 RAL + XTC + (TAF or TDF)
INSTI + 1 NRTI
 DTG/3TC
Recommended in Certain Clinical Situations
INSTI + 2 NRTIs
 EVG/COBI/FTC/(TAF or TDF)
Boosted PI* + 2 NRTIs
 (Boosted ATV or DRV) + XTC + (TAF or TDF)
 Boosted DRV + ABC/3TC
NNRTI + 2 NRTIs
 DOR/3TC/TDF or DOR + FTC/TAF
 EFV + XTC + (TAF or TDF)
 RPV/FTC/(TAF or TDF)
When ABC, TAF, TDF Cannot Be Used
 DTG/3TC
 DRV + RTV + (3TC or RAL)
*With COBI or RTV.

What’s So Bad About 2 NRTIs + a Third Drug Anyway?
 According to current guidelines . . . not much!
TDF ABC

 However, we must consider long-term ARV toxicity . . .

 . . . and the factors that influence optimal NRTI selection
TAF
TDF
TDF
TAF

Effect of First-line TDF-Based ART on CKD Risk
 Retrospective analysis of N = 6301 treatment-naive patients (21,936 PYFU)
initiating ART with median baseline eGFR of 101 mL/min/1.73 m2
TDF + Boosted PI
No TDF + Boosted PI
TDF + NNRTI
No TDF + NNRTI
D:A:D Risk Score for CKD
PredictedCKDIncidenceRate
60
50
40
30
20
10
0
10-6 -4 -3-5 -2 -1 0 1 2 3 4 5 6 7 8 9
Flandre. AIDS. 2016;30:1433.

Meta-analysis of TAF vs TDF in Randomized Head-to-Head
Clinical Trials Using Boosters (logNaive and Switch)
Safety Outcome, n/N (log%) TAF 10 mg TDF
Effect Estimate, %
(log95% CI)
P
Value
Grade 1-4 AEs 1123/2047 (55) 834/1456 (57) -8 (-18 to 3) NS
Grade 3/4 AEs 96/1844 (5) 87/1353 (6) 0 (-2 to 2) NS
Grade 3/4 lab abnormalities 345/1284 (27) 316/1078 (29) -2 (-15 to 11) NS
Serious AEs 165/1999 (8) 150/1504 (10) 0 (-2 to 1) NS
Deaths (any cause) 2/1732 (< 1) 3/1295 (< 1) 0 (0) NS
Bone fractures Wk 48 3/978 (< 1) 8/925 (1) -1 (-1 to 0) .04
D/c for bone AEs 0/1081 (0) 6/975 (1) -1 (-1 to 0) .03
D/c for renal AEs 1/2150 (< 1) 17/1506 (1) -1 (-1 to 0) .002
Hill. J Virus Erad. 2018;4:72.

A Sensible/Controversial Policy in England
 Limited FTC/TAF market
 Estimated savings from rollout
of generic FTC/TDX and
EFV/FTC/TDX in 2019/20
‒ TDX represents different salt
formulations of tenofovir
disoproxil
 Predicted savings from branded
price reductions (eg, RPV/FTC/
TDF)
Slide credit: clinicaloptions.comWaters. BHIVA Autumn Conference 2019.

HIV Regimens
Approved in 2017-2019

3 2
New Oral Fixed-Dose Combinations
3-Drug Regimens
 Bictegravir (BIC)/FTC/TAF
 Doravirine (DOR)/3TC/TDF
 Darunavir (DRV)/COBI/FTC/TAF
2-Drug Regimens
 Dolutegravir (DTG)/RPV
 Dolutegravir (DTG)/3TC

BIC/FTC/TAF
 Available only as FDC[1]
 Pros: favorable DDI profile, no emergent
resistance in first-line trials, less nausea
and better PROs vs DTG/ABC/3TC[2]
 Cons: polyvalent cation DDI,[1]
no data in
advanced HIV, weight gain[3]
 First-line
‒ GS-1489: BIC/FTC/TAF noninferior to
DTG/ABC/3TC at Wk 48[4]
and Wk 96[5]
DTG + FTC/TAF at Wk 48[6]
and Wk 96[7]
 Maintenance
continued DTG + ABC/3TC at Wk 48[8]
continued bPI + FTC/TDF or ABC/3TC at
Wk 48[9]
Key Trials
1. BIC/FTC/TAF EPAR. 2. Wohl. Patient. 2018;11:561. 3. Sax. Clin Infect Dis. 2019;[Epub]. 4. Gallant. Lancet. 2017;390:2063. 5. Wohl. Lancet HIV.
2019;6:e355. 6. Sax. Lancet. 2017;390:2073. 7. Stellbrink. Lancet HIV. 2019;6:e364. 8. Molina. Lancet HIV. 2018;5:e357. 9. Daar. Lancet HIV. 2018;5:e347.
“BIC/FTC/TAF is indicated for the treatment of adults
infected with HIV without present or past evidence of
viral resistance to the INSTI class, FTC, or tenofovir.”[1]
“BIC/FTC/TAF is indicated for the treatment of adults
infected with HIV without present or past evidence of
viral resistance to the INSTI class, FTC, or tenofovir.”[1]

DOR/3TC/TDF
 DOR: “third generation” NNRTI with
unique structure; available as a single
drug and FDC with 3TC/TDF[1,2]
 Pros: no food requirement, low DDI
potential, distinctive resistance profile vs
other NNRTIs, lipids
 Cons: resistance to both DOR and NRTIs
at failure, no head-to-head trials with
unboosted INSTIs to date
 First-line
‒ DRIVE-AHEAD: DOR/3TC/TDF noninferior
to EFV/FTC/TDF at Wk 48[3]
and Wk 96[4]
‒ DRIVE-FORWARD: DOR + 2 NRTIs
noninferior to DRV + RTV + 2 NRTIs at
Wk 48,[5]
greater efficacy at Wk 96[6]
‒ DRIVE-BEYOND: very limited data in
transmitted NNRTI resistance[7]
 Maintenance
‒ DRIVE-SHIFT: DOR/3TC/TDF noninferior
to continued 2 NRTIs + 3rd agent at
Wk 48[8]
1. DOR EPAR. 2. DOR/3TC/TDF EPAR. 3. Orkin. Clin Infect Dis. 2019;68:535. 4. Orkin. IDWeek 2018. Abstr LB1. 5. Molina. Lancet
HIV. 2018;5:e211. 6. Molina. Lancet HIV. 2019;[Epub]. 7. Wong. JAIDS. 2019;82:e47. 8. Johnson. JAIDS. 2019;81:463.
“DOR/3TC/TDF is indicated for the treatment of adults
infected with HIV without past or present evidence of
resistance to the NNRTI class, 3TC, or tenofovir.”[2]
“DOR/3TC/TDF is indicated for the treatment of adults
infected with HIV without past or present evidence of
resistance to the NNRTI class, 3TC, or tenofovir.”[2]
Key Trials

DRV/COBI/FTC/TAF
 The first (and only) PI-based single-tablet
regimen[1]
 Pros: genetic barrier, previous experience
with DRV in difficult-to-treat populations
 Cons: food requirement,[1]
DDIs,[1]
CVD?[2,3]
 First-line
‒ AMBER: DRV/COBI/FTC/TAF noninferior
to DRV/COBI + FTC/TDF at Wk 48 with
improved renal and bone parameters,[4]
efficacy/safety maintained to Wk 96[5]
 Maintenance
‒ EMERALD: DRV/COBI/FTC/TAF
noninferior to continued bPI + FTC/TDF at
Wk 48 with improved renal and bone
parameters, no resistance at failure,[6]
efficacy/safety maintained to Wk 96[7]
1. DRV/COBI/FTC/TAF EPAR. 2. Opsomer. Drugs R D. 2018;18:199. 3. Ryom. Lancet HIV. 2018;5:e291. 4. Eron. AIDS. 2018;32:1431.
5. Orkin. AIDS. 2019;[Epub]. 6. Orkin. Lancet HIV. 2018;5:e23. 7. Eron. Antiviral Res. 2019;170:104543.
“DRV/COBI/FTC/TAF is indicated for the treatment of
HIV infection in adults and adolescents (aged ≥ 12 yrs
with body weight ≥ 40 kg). Genotypic testing should
guide the use of DRV/COBI/FTC/TAF.”[1]
“DRV/COBI/FTC/TAF is indicated for the treatment of
HIV infection in adults and adolescents (aged ≥ 12 yrs
with body weight ≥ 40 kg). Genotypic testing should
guide the use of DRV/COBI/FTC/TAF.”[1]
Key Trials

DTG/RPV
 Only studied in maintenance setting
 Pros: NRTI free, improved treatment
satisfaction after switch to DTG + RPV[1]
 Cons: polyvalent cation and acid-reducing
agent DDIs,[2]
food requirement,[2]
NNRTI
resistance,[2]
no first-line data
 Maintenance
‒ SWORD-1/2: DTG + RPV noninferior to
continued 3-drug ART at Wk 48[3]
‒ Substudy of patients receiving TDF at
baseline demonstrated improvement in
BMD, bone turnover markers with switch
to DTG + RPV vs continued 3-drug ART[4]
‒ Efficacy/safety maintained to Wk 100[5]
and Wk 148[6]
analyses
‒ Confirmed virologic withdrawal has
occurred in 11/990 (1%) DTG + RPV
recipients
‒ RAMs: NNRTI, n = 6; INSTI, n = 0
1. Oglesby. Glasgow 2018. Abstr P101. 2. DTG/RPV EPAR. 3. Llibre. Lancet. 2018;391:839.
4. McComsey. AIDS. 2018;32:477. 5. Aboud. Lancet HIV. 2019;6:e576. 6. van Wyk. BHIVA 2019. Abstr P008.
“DTG/RPV is indicated for the treatment of HIV
infection in adults who are virologically suppressed on
a stable ARV regimen for ≥ 6 mos with no history of VF
and no known or suspected resistance to any NNRTI or
INSTI.”[2]
“DTG/RPV is indicated for the treatment of HIV
infection in adults who are virologically suppressed on
a stable ARV regimen for ≥ 6 mos with no history of VF
and no known or suspected resistance to any NNRTI or
INSTI.”[2]
Key Trials

DTG/3TC
 “Game changer” for 2-drug therapy?
 Pros: no ABC/TAF/TDF, no resistance at
failure in trials
 Cons: potential for HBV resistance if
used in HBV coinfection, for reduced
activity with baseline 3TC resistance;
limited data in advanced HIV
‒ Underperformance at CD4+ cell count
≤ 200 cells/mm3
; however, only 3/20 with
Snapshot nonresponse in this subgroup
had confirmed virologic withdrawal[1]
 First-line
‒ GEMINI-1/2: DTG + 3TC noninferior to
DTG + FTC/TDF at Wk 48[3]
and Wk 96[4]
with renal and bone biomarker
advantages
 Maintenance
‒ TANGO: DTG/3TC noninferior to
continued TAF-based 3-drug or
4-drug ART at Wk 48 with generally
similar AE profiles[5]
1. van Wyk. IDWeek 2019. Abstr 2842. 2. DTG/3TC EPAR. 3. Cahn. Lancet. 2019;393:143.
4. Cahn. IAS 2019. Abstr WEAB0404LB. 5. van Wyk. IAS 2019. Abstr WEAB0403LB. Slide credit: clinicaloptions.com
“DTG/3TC is indicated for the treatment of HIV infection in
adults and adolescents > 12 yrs of age weighing ≥ 40 kg, with
no known or suspected resistance to the INSTI class or 3TC.”[2]
Key Trials

 “Game changer” for 2-drug therapy?
 Pros: no ABC/TAF/TDF, no resistance at
failure in trials
 Cons: potential for HBV resistance if
used in HBV coinfection, for reduced
activity with baseline 3TC resistance;
limited data in advanced HIV
‒ Underperformance at CD4+ cell count
≤ 200 cells/mm3
; however, only 3/20 with
Snapshot nonresponse in this subgroup
had confirmed virologic withdrawal[1]
 First-line
‒ GEMINI-1/2: DTG + 3TC noninferior to
DTG + FTC/TDF at Wk 48[3]
and Wk 96[4]
with renal and bone biomarker
advantages
 Maintenance
‒ TANGO: DTG/3TC noninferior to
continued TAF-based 3-drug or
4-drug ART at Wk 48 with generally
similar AE profiles[5]
DTG/3TC
Key Trials
Are trial patients with low CD4+ cell counts
representative of advanced HIV?
 Most CDC-C diagnoses excluded
 Complex DDIs excluded
 Some with low CD4+ cell counts have very early HIV
1. van Wyk. IDWeek 2019. Abstr 2842. 2. DTG/3TC EPAR. 3. Cahn. Lancet. 2019;393:143.
4. Cahn. IAS 2019. Abstr WEAB0404LB. 5. van Wyk. IAS 2019. Abstr WEAB0403LB.

Factors to Consider
 HBV infection/immunity
 Known or suspected resistance
 Concomitant medication
 Food requirement
 Adherence
 Tolerability
 Toxicity

Guidelines: Addressing Poor Adherence
 DHHS 2019[1]
‒ In “patients with [a] history of poor adherence to non-ARV medications or
inconsistent engagement in care, consider using regimens with a boosted
PI or BIC or DTG, [which] have a high genetic barrier to resistance”
 EACS 2019[2]
‒ Indications for switch in virologically suppressed persons include regimen
fortification: “ . . . increasing the genetic barrier of a regimen in order to
prevent resistance (eg, in persons with reduced adherence)”
1. DHHS Guidelines. December 2019. 2. EACS Guidelines. November 2019. Slide credit: clinicaloptions.com

Virologic Suppression Rates by Patient Adherence
81
< 95%
97
≥ 95%
96
≥ 95%
86
< 95%
BIC/FTC/TAF (logn = 314) DTG/ABC/3TC (logn = 315)
0
40
60
80
100
HIV-1RNA<50c/mLatWk48(log%)
84
< 95%
94
≥ 95%
94
≥ 95%
90
< 95%
BIC/FTC/TAF (logn = 320) DTG + FTC/TAF (logn = 325)
GS-1490[2]
GS-1489[1]
1. Gallant. Lancet. 2017;390:2063. 2. Sax. Lancet. 2017;390:2073.
20
0
40
60
80
100
HIV-1RNA<50c/mLatWk48(log%)
20

Weight Change at Wk 96 Across First-line RCTs
Trials not head-to-head with differences in baseline demographics (eg, sex, race, age, weight).
1. Wohl. Lancet HIV. 2019;6:e355. 2. Stellbrink. Lancet HIV. 2019;6:e364.
3. Cahn. IAS 2019. Abstr WEAB0404LB. 4. Hill. IAS 2019. Abstr MOAX0102LB.
0
2.4
DTG/ABC/
3TC
3.6
BIC/FTC/
TAF
3.5
BIC/FTC/
TAF
3.9
DTG +
FTC/TAF
Study 1489[1]
Study 1490[2]
4
6
8
10
WeightΔFromBaseline(logkg)
2
Mean Weight GainMedian Weight Gain
2.1
3.1
8
5
2
GEMINI[3]
ADVANCE[4]
DTG +
3TC
DTG +
FTC/TDF
DTG +
FTC/TAF
DTG +
FTC/TDF
EFV/FTC/
TDF
n = 314 315 320 325 716 717 351 351 351

*
*
*
*
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)
Slide credit: clinicaloptions.comSax. Clin Infect Dis. 2019;[Epub].
*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(log95%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
*
*
*
*
*
*
*
* *
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*

Pharmacogenomics . . . It’s All Gone a Bit Quiet

Individualized Choice: What and When
 Patient factors
‒ Choice should be determined by the factors we understand now and the
factors that emerge in the future
 Not systems factors!
‒ Choice should not be determined by systems factors

Improved Clinical Outcomes With Rapid ART Initiation
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 (log95% 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)
 Systematic review of rapid ART initiation among 4 RCTs[1]
‒ Increased likelihood of ART
initiation, retention in care,
viral suppression
‒ Trend for decreased
likelihood of loss to follow-up
and death
Same-day ART associated with:
 In addition, earlier ART initiation reduces the viral reservoir in the individual[2-5]
1. Ford. AIDS. 2018;32:17. 2. Tagarro. JAIDS. 2018;79:269. 3. Luo. BMC Infect Dis. 2019;19:257.
4. Jain. J Infect Dis. 2013;208:1202. 5. Buzon. J Virol. 2014;88:10056.

Rapid Initiation of ART: WHO Recommendations
 “Rapid ART initiation should be offered to all people living with HIV
following a confirmed diagnosis and clinical assessment”
 “ART initiation should be offered on the same day to people who are
ready to start”
 Special considerations
‒ Symptomatic patients with signs of TB or cryptococcal meningitis should
first start with anti-TB/antifungal drugs before initiating ARVs
Slide credit: clinicaloptions.comhttps://www.who.int/hiv/pub/guidelines/advanced-HIV-disease/en/.

Recommended First-line Regimens in EACS Guidelines
 INSTI + 2 NRTIs (logPreferred)
‒ DTG/ABC/3TC
‒ DTG + FTC/TAF or XTC/TDF
‒ BIC/FTC/TAF
‒ RAL + FTC/TAF or XTC/TDF
 INSTI + 1 NRTI
‒ DTG + 3TC
 NNRTI + 2 NRTIs
‒ DOR/3TC/TDF
‒ DOR + FTC/(TAF or TDF)
‒ RPV/FTC/(TAF or TDF)
‒ RPV + 3TC/TDF
 Boosted PI + 2 NRTIs
‒ DRV/COBI/FTC/TAF
‒ DRV/COBI + XTC/TDF
‒ DRV + RTV + FTC/TAF or XTC/TDF
EACS Guidelines. November 2019. Slide credit: clinicaloptions.com

 NNRTI + 2 NRTIs
‒ DOR/3TC/TDF
‒ DOR + FTC/(TAF or TDF)
‒ RPV/FTC/(logTAF or TDF) (log< 100,000 c/mL)
‒ RPV + 3TC/TDF (log< 100,000 c/mL)
 Boosted PI + 2 NRTIs
‒ DRV/COBI/FTC/TAF
‒ DRV/COBI + XTC/TDF
‒ DRV + RTV + FTC/TAF or XTC/TDF
Recommended First-line Regimens in EACS Guidelines:
Baseline HIV-1 RNA Constraints for Use
 INSTI + 2 NRTIs (logPreferred)
‒ DTG/ABC/3TC
‒ DTG + FTC/TAF or XTC/TDF
‒ BIC/FTC/TAF
‒ RAL + FTC/TAF or XTC/TDF
 INSTI + 1 NRTI
‒ DTG + 3TC (log< 500,000 c/mL)
EACS Guidelines. November 2019. Slide credit: clinicaloptions.com

DTG + 2 NRTIs
BIC/FTC/TAF
DOR + 2 NRTIs
bPI + 2 NRTIs
Dual Therapy
Choosing
Wisely
→
Dooley. Clin Infect Dis. 2019;[Epub].
 DTG should be dosed
50 mg BID when used
with rifampin-based
TB therapy

Global Status of DTG-Based ART Use
 By mid 2019, 123 LMICs (90%) included/planned to include DTG in HIV policy[1]
1. https://www.who.int/hiv/pub/arv/treat-all-uptake/en/. 2. EACS Guidelines. November 2019.
3. https://www.who.int/hiv/pub/arv/arv-update-2019-policy/en/.
Where do DTG-based regimens fit into
international first-line guidelines?
 Preferred by EACS[2]
:
DTG + ABC/3TC, FTC/TAF, or XTC/TDF
 Preferred by WHO[3]
:
DTG + XTC/TDF

-2
NAMSAL: DTG-Based ART vs Low-Dose EFV–Based ART
as First-line Therapy in Cameroon
 Multicenter, randomized, open-
label phase III noninferiority trial
DTG 50 mg + 3TC/TDF QD
(n = 310)
EFV 400 mg + 3TC/TDF QD
(n = 303)
Wk 48
ART-naive adults
with HIV-1 RNA
≥ 1000 copies/mL
(N = 613)
Slide credit: clinicaloptions.comNAMSAL ANRS 12313 Study Group. NEJM. 2019;381:816.
 Primary endpoint: HIV-1 RNA
< 50 copies/mL at Wk 48 by
FDA Snapshot in ITT population
(noninferiority margin: -10%)
ITT
HIV-1RNA<50copies/mL(log%)
Wk
0
20
40
60
80
100
75
69
4 12 24 48
Treatment difference: 5.5% (95% CI: -1.6% to 12.7%)
P < .001 for noninferiority, P = .13 for superiority
DTG
EFV400

NAMSAL: Kinetics of Viral Suppression by HIV-1 RNA
Level at ScreeningHIV-1RNA<50copies/mL(log%)
DTG, VL < 100,000 c/mL EFV400, VL < 100,000 c/mL
EFV400, VL 100,000 to < 500,000 c/mLDTG, VL 100,000 to < 500,000 c/mL
DTG, VL ≥ 500,000 c/mL EFV400, VL ≥ 500,000 c/mL
Wks
0
20
40
60
80
100
-2 4 12 24 48
Calmy. WHO Guidelines Meeting to Update the ARV Recommendations. June 2019. Data adapted from Cournil. Glasgow 2018. Abstr O342.
Lowest virologic suppression rates
in patients with HIV-1 RNA
≥ 500,000 c/mL at entry

ADVANCE: DTG + FTC/TAF vs DTG + FTC/TDF vs EFV/FTC/
TDF as First-line Therapy in South Africa
 Randomized, open-label phase III
noninferiority trial
ART-naive patients
(≥ 12 yrs) with
HIV-1 RNA ≥ 500
copies/mL; no
current TB tx or
pregnancy
(N = 1053)
DTG 50 mg + FTC/TAF QD
(n = 351)
DTG 50 mg + FTC/TDF QD
(n = 351)
EFV 600 mg/FTC/TDF QD
(n = 351)
 Primary endpoint: HIV-1 RNA
< 50 copies/mL at Wk 48 by
FDA Snapshot in ITT population
(noninferiority margin: -10%)
Venter. NEJM. 2019;381:803.
ITT
HIV-1RNA<50copies/mL(log%)
Wk
85
84
79
DTG + FTC/TAF
DTG + FTC/TDF
EFV/FTC/TDF
0
20
40
60
80
100
0 4 12 24 36 48
Wk 96
Treatment differences
D/TAF vs EFV: 5.1% (98.3% CI: -1.9% to 12.2%); P = .08
D/TDF vs EFV: 6.3% (98.3% CI: -0.1% to 13.2%); P = .03
D/TAF vs D/TDF: -1.1% (98.3% CI: -7.7% to 5.4%); P = .68

Tsepamo: Prevalence of NTDs by ARV Use, July 2019
At Conception
DTG During
Pregnancy
HIV Negative
DTG Non-DTG EFV
Total NTDs per exposures, n/N 5/1683 15/14,792 3/7959 1/3840 70/89,372
 Prevalence difference, % (95% CI) Reference 0.20
(0.01-0.59)
0.26
(0.07-0.66)
0.27
(0.06-0.67)
0.22
(0.05-0.62)
NTDs per exposures since May 2018, n/N 1/1257 1/3492 0/2172 1/1028 9/23,315
DeliveriesWithNeural
TubeDefect(log%)
0.30
0.10 0.08
0.5
1.0
0 0.04 0.03
“99.8% of the
women for whom
folate was
prescribed started
taking folate during,
not before,
pregnancy”
Zash. NEJM. 2019;381:827. Zash. IAS 2019. Abstr MOAX0105LB.

Tsepamo: Prevalence of NTDs by ARV Use, July 2019
At Conception
DTG During
Pregnancy
HIV Negative
DTG Non-DTG EFV
Total NTDs per exposures, n/N 5/1683 15/14,792 3/7959 1/3840 70/89,372
 Prevalence difference, % (95% CI) Reference 0.20
(0.01-0.59)
0.26
(0.07-0.66)
0.27
(0.06-0.67)
0.22
(0.05-0.62)
NTDs per exposures since May 2018, n/N 1/1257 1/3492 0/2172 1/1028 9/23,315
DeliveriesWithNeural
TubeDefect(log%)
0.30
0.10 0.08
0.5
1.0
0 0.04 0.03
“99.8% of the
women for whom
folate was
prescribed started
taking folate during,
not before,
pregnancy”
1. Zash. NEJM. 2019;381:827. 2. Cabrera. AIDS. 2019;33:1967.
 Could DTG cause NTDs directly or
could the cause be environmental
factors (eg, no folate supplementation
of flour/grains in Botswana[1]
)?
 DTG is a partial antagonist of folate
receptor 1 (FOLR1)[2]

WHO and EACS Guidance on DTG Use at Conception
 EACS: DTG not recommended in women who
wish to conceive or who become pregnant
while on ART; ok after 8 wks of pregnancy[1]
https://www.who.int/news-room/detail/22-07-2019-who-recommends-dolutegravir-as-preferred-hiv-treatment-option-in-all-populations
1. EACS Guidelines. November 2019. 2. WHO Policy Brief on First-line and Second-line ART. July 2019. Slide credit: clinicaloptions.com
“DTG can be prescribed for adult
women and adolescent girls of
childbearing age or potential who
wish to become pregnant or who are
not otherwise using or accessing
consistent and effective contraception
if they have been fully informed of
the potential increase in the risk of
neural tube defects (at conception
and until the end of the first
trimester)”[2]

DTG + 2 NRTIs
BIC/FTC/TAF
DOR + 2 NRTIs
bPI + 2 NRTIs
Dual Therapy
Choosing
Wisely
 BID dosing of
BIC/FTC/TAF with
rifampin does not
sufficiently mitigate
induction effect to yield
therapeutic doses of BIC/
FTC/TAF seen in phase III
trials
Custodio. CROI 2018. Abstr 34.
→

GS-1490: BIC/FTC/TAF vs DTG + FTC/TAF as First-line
Therapy in International Trial
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (noninferiority margin: -12%)[1]
‒ BIC/FTC/TAF vs DTG + FTC/TAF: 89% vs 93% (difference: -3.5%; 95% CI: -7.9% to 1.0%; P = .12)
 No treatment-emergent resistance detected in any patient through Wk 96[2]
BIC/FTC/TAF (n = 320)
Favors
BIC/FTC/TAF
Patients(log%)
100
80
60
40
20
0
84 86
HIV-1 RNA
< 50 c/mL
HIV-1 RNA
≥ 50 c/mL
4 3
12 11
DTG + FTC/TAF (n = 325)
No Virologic
Data
Virologic Outcomes at Wk 96[2]
Favors
DTG + FTC/TAF
Treatment Difference at Wk 96, % (log95% CI)[2]
-12 -6 0 6 12
-2.3
-7.9 3.2
1. Sax. Lancet. 2017;390:2073. 2. Stellbrink. Lancet HIV. 2019;6:e364.

DTG + 2 NRTIs
BIC/FTC/TAF
DOR + 2 NRTIs
bPI + 2 NRTIs
Dual Therapy
Choosing
Wisely →
1. Yee. CROI 2015. Abstr 521. 2. DOR EPAR.
 Multiple-dose rifampin
significantly reduced DOR
AUC0-∞, Cmax, and C24
[1]
‒ Rifampin
coadministration
contraindicated[2]

73.1
66.0
DRV + RTV
+ 2 NRTIs
(logn = 383)
DOR
+ 2 NRTIs
(logn = 383)
DOR/3TC/
TDF
(logn = 364)
77.5 73.6
EFV/FTC/
TDF
(logn = 364)
DOR + 2 NRTIs vs EFV or (logDRV + RTV) + 2 NRTIs
in Treatment-Naive Adults
 Resistance analyses at Wk 96
‒ DRIVE-AHEAD: 1.6%
with DOR-R vs 3.8% with
EFV-R; NRTI-R in 1.4% vs
1.6%, respectively
‒ DRIVE-FORWARD:
DOR + NRTI resistance,
n = 2; NRTI resistance but no
PI resistance, n = 1; lipid
changes more favorable
with DOR vs DRV + RTV
HIV-1RNA<50copies/mL
atWk96(log%)
0
20
40
60
80
100
1. Orkin. IDWeek 2018. Abstr LB1. 2. Molina. Lancet HIV. 2019;[Epub].
DRIVE-AHEAD[1]
DRIVE-FORWARD[2]
Treatment difference:
3.8% (95% CI: -2.4% to 10.0%)
Treatment difference:
7.1% (95% CI: 0.5% to 13.7%)

DTG + 2 NRTIs
BIC/FTC/TAF
DOR + 2 NRTIs
bPI + 2 NRTIs
Dual Therapy
Choosing
Wisely
→
 High risk of DDIs

AMBER: DRV/COBI/FTC/TAF vs DRV/COBI + FTC/TDF
in Treatment-Naive Adults
4% 6%
4% 9%
DRV/COBI/FTC/TAF (logn = 362)
Wk 48
3% 4%
8% 12%
DRV/COBI + FTC/TDF (logn = 363)
Wk 48Wk 96 Wk 96
HIV-1 RNA ≥ 50 c/mL
No virologic data
HIV-1RNA<50c/mL(log%)
91 8885 84
 Patients receiving DRV/COBI +
FTC/TDF switched to
DRV/COBI/FTC/TAF at Wk 48
 Resistance analysis of 9/15 patients
with PDVF in DRV/COBI/FTC/TAF arm
vs 8/19 in control arm through Wk 96
‒ 1 patient with M184V/I in each arm
‒ No evidence of emergent DRV,
primary PI, or TFV RAMs
FDA Snapshot Analysis (logITT)
0
20
40
60
80
100
Orkin. Glasgow 2018. Abstr O212.

Drug–Drug Interaction Risk: Differences Among ARVs
No interaction
Potential weak interaction
Interaction of clinical relevance
Drugs should not be coadministered
Efavirenz Rilpivirine Doravirine
Boosted ARV BictegravirRaltegravir Dolutegravir
Etravirine
Slide credit: clinicaloptions.comCourtesy of Dr. David Back. Data from Mixpanel analytics of https://www.hiv-druginteractions.org.

DTG + 2 NRTIs
BIC/FTC/TAF
DOR + 2 NRTIs
bPI + 2 NRTIs
Dual Therapy
Choosing
Wisely
→

GEMINI-1 and -2: DTG + 3TC in ART-Naive Adults
 Parallel, international, randomized, double-blind phase III noninferiority studies
 Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA Snapshot
(noninferiority margin of -10%)
ART-naive adults with
HIV-1 RNA 1000-500,000 copies/mL,
≤ 10 days on previous ART, no major
RT or PI resistance mutations, no HBV
infection or HCV requiring therapy
(N = 1433)
DTG + 3TC PO QD
(n = 716)
DTG + FTC/TDF PO QD
(n = 717)
Wk 148
Primary Endpoint
Wk 48
Stratified by HIV-1 RNA (≤ vs > 100,000 copies/mL),
CD4+ cell count (≤ vs > 200 cells/mm³)
Study comprises screening period up to 35 days; double-blinded until Wk 96, open-label until Wk 148.
Continuation of
DTG + 3TC
permitted
Cahn. Lancet. 2019;393:143. NCT02831673. NCT02831764.

Responders by
Analysis, % (logn)
DTG + 3TC
(logn = 716)
DTG + FTC/TDF
(logn = 717)
Difference, %
(log95% CI)
Snapshot 86.0 (616) 89.5 (642) -3.4 (-6.7 to 0)*
TRDF†
96.6 (692) 96.4 (691) 0.2 (-1.8 to 2.2)
GEMINI-1 and -2: Virologic Response
 DTG + 3TC met Snapshot criteria for noninferior efficacy vs DTG + FTC/TDF at Wk 96
*Adjusted for baseline HIV-1 RNA, baseline CD4+ cell count, and study.
†
Accounts for CVW, withdrawal for lack of efficacy or treatment-related AE, and participants meeting protocol-defined stopping criteria.
HIV-1RNA<50copies/mL
bySnapshot,%(log95%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. IAS 2019. Abstr WEAB0404LB.

 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
ADVANCE: Mean Change in Weight by Sex
Wk
Women
MeanWeightChange(logkg)
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(logkg)
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.

Indications for Switch in Virologically Suppressed
Persons
 Documented toxicity or
prevention of long-term toxicity
 Avoidance of DDIs
 Aging and/or comorbidity
 Simplification
 Planned pregnancy or women
wishing to conceive
 Protection from HBV
 Regimen fortification
 Cost reduction
Slide credit: clinicaloptions.comEACS Guidelines. November 2019.
“Clinicians should always review possible AEs or tolerability
issues with current ARV regimens. Just because the viremia is
suppressed, it should not be assumed that the PLWH is well
adapted and tolerating the current regimen”

Guidelines Recommendations on Proviral Genotyping
Slide credit: clinicaloptions.com1. EACS Guidelines. November 2019. 2. DHHS Guidelines. October 2018.
DHHS 2018[2]
EACS 2019[1]

D:A:D Study: Increased CVD Risk With Boosted PIs
 Increased CVD risk with RTV-boosted DRV in unadjusted and multivariate analyses
Slide credit: clinicaloptions.comRyom. Lancet HIV. 2018;5:e291.
RTV-Boosted ATV RTV-Boosted DRV
CVDIncidenceRate,
Events/1000PYFU(log95%CI) Unadjusted Incidence of CVD Stratified by Cumulative PI Use
20
15
10
5
1
0
0 0-1 1-2 2-3 3-4 4-5 5-6 > 6
Cumulative Yrs of Exposure
Events, n
PYFU
824
163,785
75
12,886
49
7631
41
6369
26
6144
46
5757
34
4898
62
9278
0 0-1 1-2 2-3 3-4 4-5 5-6 > 6
Cumulative Yrs of Exposure
909
185,246
52
8845
51
6591
44
5285
39
4100
17
2940
18
1768
27
1975

Cardiovascular Safety of Switch From TDF to TAF
 Retrospective observational study of virologically suppressed PLWH
switching TDF to TAF after ≥ 1 yr of stable ART (N = 110)
‒ Mean age: 50 yrs
‒ 73% male, 65% overweight or obese, 58% black, 49% receiving INSTIs
 In regression analysis comparing values from 1 yr before and after ART
modification, switch to TAF associated with significant increases in:
‒ BMI: 0.45 (95% CI: 0.14-0.76)
‒ ASCVD risk score: 13% (95% CI: 4% to 23%)
‒ Shifted 50.7% of patients to scores indicating use of a statin
Slide credit: clinicaloptions.comSchafer. Open Forum Infect Dis. 2019;6:ofz414.

-25
NEAT022: Switch From Boosted PI to DTG in Suppressed
Patients With High CV Risk
 Patients with stable HIV-1 RNA < 50 copies/mL on PI/RTV + 2 NRTIs, high CV risk (> 50 yrs of age and/or
Framingham risk score > 10% at 10 yrs), no resistance, no VF randomized to continue PI/RTV or switch
to DTG with no change in NRTIs (N = 415)
 No emergent resistance in patients with VF
Virologic
Success*
Virologic
Nonresponse
No Virologic
Data
ITTPatientsatWk48
(log%)
Treatment difference: -2.1%
(95% CI: -6.6% to 2.4%)
5 4
100
80
60
40
20
0
93 95
2 < 1
DTG + 2 NRTIs
PI/RTV + 2 NRTIs
*HIV-1 RNA < 50 copies/mL (coprimary endpoint with change
in total cholesterol).
DTG + 2 NRTIs
PI/RTV + 2 NRTIs
0.7
-8.7
-11.3
0.5
4.2
2.0 1.1
2.5
0.4
-18.4
-7.7 -7.0
TC Non–
HDL-C
TG LDL-C HDL-C TC/HDL
Ratio
P < .001
P < .001
P < .001
P < .001 P < .001
P = .286
MeanChange
FromBLtoWk48(log%)
5
-5
-15
10
0
-10
-20
Gatell. AIDS. 2017;31:2503. Slide credit: clinicaloptions.com

Considering DDIs: Example Interaction Reports for
Metformin
Slide credit: clinicaloptions.comhttps://www.hiv-druginteractions.org/checker.

BIC vs DTG: Coadministration With Metformin
 Coadministration of metformin (850 mg
QD then 500 mg BID) with BIC/FTC/TAF
(50/200/25 mg QD) was studied in 32
healthy subjects[1]
‒ Use of BIC/FTC/TAF increased metformin
Cmax by 28%, AUC by 39%
 No dose adjustment of metformin
required in patients with normal renal
function receiving BIC/FTC/TAF[2]
‒ If moderate renal impairment, consider
close monitoring due to increased risk for
lactic acidosis and dose adjustment of
metformin if necessary
 Coadministration of metformin 500 mg
BID with DTG 50 mg QD or BID was
studied in 30 healthy subjects[3]
‒ Use of DTG 50 mg QD increased
metformin Cmax by 66%, AUC by 79%
 Consider dose adjustment of metformin
when starting/stopping coadministration
of DTG to maintain glycemic control[4]
‒ US prescribing information suggests
limiting total daily dose of metformin to
1000 mg when starting DTG[5]
Slide credit: clinicaloptions.com1. Custodio. IDWeek 2017. Abstr 1386. 2. BIC/FTC/TAF EPAR. 3. Song. JAIDS. 2016;72:400. 4. DTG EPAR. 5. DTG PI.

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