Key Slides on Integrating the Latest HIV Treatment

Safety and Tolerability Data Into Clinical Practice

Supported by an educational grant from Janssen Therapeutics,

Division of Janssen Products, LP
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Faculty
Kassem Bourgi, MD
Assistant Professor of Medicine
Infectious Disease and Internal Medicine
Eskenazi Health
Indiana University
Indianapolis, IN

Kassem Bourgi, MD, has disclosed that he has received funds for research
support from Gilead Sciences.
ART and Weight Gain
Patient Case 1: Background
 34-yr-old treatment-naive black Parameter at Current
Value
Presentation
MSM, CrossFit trainer diagnosed
CD4+ cell count, cells/mm3 523
with HIV 1 month ago HIV-1 RNA, copies/mL 187,000
 Nonsmoker; occasional use of HIV-1 genotype Wild type
HLA-B*5701 Negative
marijuana, and alcohol
BMI 22.5
 BMI 22.5 Glucose, mg/dL 95
CrCl, mL/min 99
 Patient is ready to start HIV HBV Immune
therapy but wants an STR “that HCV antibody Negative
won’t make me gain excessive
weight” *Other CBC parameters normal.
 International Guidance on First-line ART
DHHS[1] IAS-USA[2] EACS[3] WHO[4]
Recommended Initial Generally Recommended Recommended Regimens Preferred First-line
Regimens for Most PWH Initial Regimens (Preferred) Regimen
 BIC/FTC/TAF  BIC/FTC/TAF  BIC/FTC/TAF  DTG + XTC/TDF
 DTG/3TC*  DTG/ABC/3TC  DTG/ABC/3TC
 DTG/ABC/3TC  DTG + FTC/TAF  DTG + FTC/TAF or XTC/TDF
 DTG + XTC + (TAF or TDF)  RAL + FTC/TAF or XTC/TDF
 RAL + XTC + (TAF or TDF)
Recommended Regimens
 DOR + FTC/TAF or XTC/TDF
 DRV + (COBI or RTV) +
(FTC/TAF or XTC/TDF)
 DTG + 3TC
 RPV + FTC/TAF or XTC/TDF

*Except when HIV RNA > 500,000 copies/mL, HBV coinfected, or ART to be started before RT genotypic resistance testing or HBV testing results
available.
1. DHHS Guidelines. December 2019. 2. Saag. JAMA. 2018;320:379.
3. EACS Guidelines. November 2019. 4. WHO Policy Brief. July 2019. Slide credit: clinicaloptions.com
 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)
Black female
Female Black Black male
Male Nonblack Nonblack female
Nonblack male
LS Mean Weight Δ, kg (95% CI)

4.5 5.0 6
*† *
†
* *

LSM Weight Change (kg)

LSM Weight Change (kg)

4.0 * 4.5 *†
* 4.0 * 5 * †
3.5 * *
3.0 3.5 4 *† *
†

3.0 * *
2.5 2.5 3
2.0 * *
2.0
1.5 1.5 2
*
1.0 1.0 1
0.5 0.5
0 0 0
12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 108
Wks Wks Wks
*Color-coded to match respective comparators, denoting P < .05 vs male (first panel), nonblack (second panel), or nonblack females
(last panel). †P < .05 vs black males.
Sax. Clin Infect Dis. 2019;[Epub]. Slide credit: clinicaloptions.com
 Weight Gain Following ART Initiation by ARV Class and
ARV Drug

INSTI BIC TAF

LS Mean Weight Δ, kg (95% CI)

LS Mean Weight Δ, kg (95% CI)

LS Mean Weight Δ, kg (95% CI)

4 PI 6 DTG 6 ABC
NNRTI * * EVG/COBI * * TDF * *
* 5 * * * 5 ZDV * *
3 * * * * *
* * * * **
* * 4 * * 4 * *
* * *
2 * 3 3 *
* * * *
*
2 2
1
1 1
0 0 0
12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96 12 24 36 48 60 72 84 96
Wks Wks Wks

*Color-coded to match respective comparators, denoting P ≤ .05 vs NNRTI (first panel), EVG/COBI (second panel), or ZDV (last panel).

Sax. Clin Infect Dis. 2019;[Epub]. Slide credit: clinicaloptions.com

 BMI Changes Over Time in PWH Initiating ART
Compared With Uninfected Persons
 Comparison of BMI over time in Change
Change in BMI
in BMI bybyHIV
HIVStatus
Status
PWH vs uninfected controls from Kaiser 32 Uninfected (N = 129,966)
Permanente EMR database PWH (N = 8256)
(N = 138,222)
0.06 kg/m2/yr (reference) 29.4
30
‒ Study included PWH ≥ 21 yrs of age 28.7

BMI, kg/m2
who initiated ART between 2006-2016
with available baseline BMI 28
28.4
‒ Uninfected controls were matched 1:10
by age, sex, race/ethnicity, clinic, yr 26

25.8 0.22 kg/m2/yr (P < .001)

 Linear mixed effects modeling* to
24
compare BMI over time by HIV status
0 2 4 6 8 10 12
and baseline BMI
Yrs From Baseline
*Potential confounders: sex, age, race/ethnicity, yr, smoking,
Silverberg. AIDS 2020. Abstr OAB0603. substance abuse disorder, education/income, insurance, comorbidities. Slide credit: clinicaloptions.com
 BMI Changes Over Time by HIV Status and Baseline BMI
Normal/Underweight Overweight Obese
(< 25.0 kg/m2) (25.0-29.9 kg/m2) (≥ 30 kg/m2)
28 Uninfected (n = 32,038) 32 Uninfected (n = 49,602) 38 Uninfected (n = 48,326)
PWH (n = 3852) PWH (n = 2927) PWH (n = 1477)
26 0.31 kg/m2/yr 25.1 30 36
0.18 kg/m2/yr 28.3 0.07 kg/m2/yr 33.5
BMI, kg/m2

(P < .001) (P < .001) 33.5 (P = .09)

24 28 34
24.2 26.3
22.0
27.4
22 0.20 kg/m2/yr
26 32 33.2
0.09 kg/m2/yr
(reference)
26.2
(reference)
32.6-0.02 kg/m2/yr (reference)
21.6
20 24 30
0 2 4 6 8 10 12 0 2 4 6 8 10 12 0 2 4 6 8 10 12
Yrs From Baseline
 Study limitations include BMI as imperfect measure (ie, does not account for muscle mass), unmeasured
confounders (diet, exercise), study population > 85% male (unclear implications for women)
Silverberg. AIDS 2020. Abstr OAB0603. Slide credit: clinicaloptions.com
 ADVANCE: Phase III Trial of First-line DTG + FTC/(TAF or
TDF) vs EFV/FTC/TDF in South Africa
 Multicenter, randomized, open-label phase III trial conducted in South Africa
Wk 48 Wk 96
Primary Endpoint Current Analysis Wk 192 Wk 96 HIV-1 RNA
< 50 c/mL*
DTG 50 mg QD + FTC/TAF QD
ART-naive patients ≥ 12 yrs of age
(n = 351) 79%
with HIV-1 RNA ≥ 500 copies/mL,
no ART in prior 6 mos, no TB or DTG 50 mg QD + FTC/TDF QD
pregnancy, no BL genotype, and (n = 351)
78%
CrCl > 60 mL/min
(N = 1053) EFV/FTC/TDF QD
(n = 351) 74%
*Differences between arms not statistically significant.

 Primary efficacy endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 by ITT (M = F) analysis

‒ DTG + FTC/TAF and DTG + FTC/TDF noninferior to EFV/FTC/TDF at Wk 48: 84% vs 85% vs 79%
 Secondary endpoints: safety, weight gain
Sokhela. AIDS 2020. Abstr OAXLB0104. Venter. NEJM. 2019;381:803. NCT03122262. Slide credit: clinicaloptions.com
 ADVANCE: Mean Change in Weight by Sex at Wk 96
 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
DTG + FTC/TAF (n = 351) DTG + FTC/TDF (n = 351) EFV + FTC/TDF (n = 351)
Men Women
14 14
12 12
Mean Weight Change (kg)

Mean Weight Change (kg)

10 10 +10 kg

P < .001
8 8

P < .001
6 6
+5 kg +5 kg

NS P < .01
4 4

P < .05
+4 kg

P < .01
+3 kg
2 2
+1 kg
0 0

0 4 12 24 36 48 60 72 84 96 0 4 12 24 36 48 60 72 84 96
Wk Wk
n = 430 418 402 387 376 374 366 292 232 140 n = 549 531 514 488 474 459 441 359 276 175
Hill. IAS 2019. Abstr MOAX0102LB. Slide credit: clinicaloptions.com
 ADVANCE: Weight Gain and Metabolic Syndrome
Through Wk 144
 Gained weight was predominantly fat mass rather than lean mass; women gained
significantly more fat mass than men (P < .001)
DTG + FTC/TAF DTG + FTC/TDF EFV/FTC/TDF
Outcome
(n = 351) (n = 351) (n = 351)
Mean weight gain from BL, kg
Women
 Wk 96 8.2 4.6 3.2
 Wk 144* 12.3 7.4 5.5

Men
 Wk 96 5.2 3.6 1.4
 Wk 144* 7.2 5.5 2.6
Treatment-emergent metabolic syndrome at Wk 96, %
All patients 8.4† 5.9 3.9†
Women 10.9 8.1 5.6
Men 4.6 3.3 1.8
*Data after Wk 96 are incomplete. †P = .03 for comparison between DTG + FTC/TAF and EFV/FTC/TDF. All other comparisons were not significant.
Sokhela. AIDS 2020. Abstr OAXLB0104. Slide credit: clinicaloptions.com
 ADVANCE Substudy: CYP2B6 Genotype and Weight Gain
Differences Between DTG and EFV
 In ADVANCE substudy, 171 patients in Weight Change From BL to Wk 48
P = 1.000
EFV/FTC/TDF arm underwent CYP2B6 P = .002 ●
40
genotyping P < .001
●
●
●
‒ SNP categories: extensive, ●
● ●
●

Weight Δ From BL (%)

● ●
●
intermediate, slow EFV metabolizers 20
●
●
●
●

 Similar weight gain for CYP2B6

extensive metabolizers receiving 0
EFV or DTG + FTC/TDF
 Higher EFV levels due to slower P = .066
●
●
-20
metabolism may suppress weight gain P = .004
Extensive Intermediate Slow DTG/FTC/TDF

Griesel. CROI 2020. Abstr 82. Slide credit: clinicaloptions.com

 Real World Data: Weight Gain With INSTI vs PI
 Data from the Decision Resources Group’s Real World Data repository on adults without
prior ART history and a submitted claim for a newly initiated PI or INSTI after July 17, 2018
(date of DRV/COBI/FTC/TAF approval)
‒ PI regimens initiated: 64.5% DRV-based STR, 11.9% ATV, 12.6% other DRV regimen, 10.9% other
‒ INSTI regimens initiated: 59.4% BIC-based, 24% DTG-based, 15% EVG-based, 1.7% RAL-based
Weight Gain or BMI Increases With INSTI vs PI
Weighted OR Patients Receiving
Weight
(95% CI) PI, INSTI, %
≥ 5% weight gain
1.47 (1.04-2.08; P = .028) 20, 26
≥ 10% weight gain
1.47 (0.90-2.38; P = .125) 8, 11
BMI
≥ 5% BMI increase 1.56 (1.11-2.17; P = .011) 20, 28
≥ 10% BMI increase 1.19 (0.76-1.89; P = .441) 11, 12

0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4
OR
Less Likely for PI-Based Regimens More Likely for INSTI-Based Regimens
Chow. AIDS 2020. Abstr PEB0194. Slide credit: clinicaloptions.com
 OPERA: Longitudinal Prospective Cohort Analysis
 Routine EHR data collected Maintained Other ARVs
Anchor Agent by Class, % (n)
from ~ 8% of US PWH (n = 5479)
receiving care (> 115,000  Elvitegravir/
individuals across 65 cities INSTIs cobicistat 73 (2389)
(n = 3281)  Dolutegravir
in 19 states and Puerto  Raltegravir
20 (643)
8 (249)
Rico)
 Rilpivirine 85 (1238)
 Current analysis restricted NNRTIs  Nevirapine 12 (176)
(n = 1452)  Efavirenz 2 (26)
to adults receiving TDF-  Etravirine 1 (12)
containing 3-drug ART at BL
with ≥ 2 consecutive HIV-1  Darunavir 68 (504)
Boosted PIs  Atazanavir 28 (211)
RNA < 200 copies/mL who (n = 746)  Lopinavir 3 (22)
switched TDF to TAF  Fosamprenavir 1 (9)

Mallon. AIDS 2020. Abstr OAB0604. Slide credit: clinicaloptions.com

 OPERA: Weight Change With Switch From TDF to TAF
While Maintaining Other ARVs by Class of Anchor Agent
INSTI NNRTI Boosted PI
92 92 92
90 90 90
88 88 88
86 86
Weight (kg)

86
84 84 84
82 82 82
80 80 80
78 78 78

0 0 0
-60-54-48-42-36-30-24-18-12-6 0 6 12 1824 30 36 4248 -60-54-48-42-36-30-24-18-12-6 0 6 12 1824 30 36 4248 -60-54-48-42-36-30-24-18-12-6 0 6 12 1824 30 36 4248
Mos From Switch
Estimated Weight Δ by Time From INSTI NNRTI Boosted PI
TDF to TAF Switch, kg/yr (95% CI) (n = 3281) (n = 1452) (n = 746)
-60 to 0 mos 0.42 (0.26 to 0.59) 0.66 (0.51 to 0.81) 0.31 (-0.02 to 0.64)
0 to 9 mos 2.64 (2.26 to 3.01) 2.25 (1.78 to 2.71) 1.98 (1.13 to 2.83)
9+ mos 0.29 (0.08 to 0.51) 0.20 (-0.14 to 0.54) -0.11 (-0.57 to -0.35)

Mallon. AIDS 2020. Abstr OAB0604. Slide credit: clinicaloptions.com

 OPERA: Weight Change With Switch From TDF to TAF
While Maintaining Other ARVs by Specific INSTI
Estimated
Weight Δ by
92 Time From TDF EVG/c DTG RAL
to TAF Switch, (n = 2389) (n = 643) (n = 249)
90
kg/yr (95% CI)
88 EVG/c
RAL
Weight (kg)

86 DTG 0.71 0.73 -0.44

84 -60 to 0 mos (-0.79 to
(0.53 to 0.90) (0.34 to 1.11) -0.08)
82
80 2.51 2.38 1.80
0 to 9 mos
(2.05 to 2.96) (1.64 to 3.13) (0.57 to 3.03)
78
-0.18 0.63
0 0.36
9+ mos (-0.64 to (-0.20 to
-60 -54 -48 -42 -36-30-24-18 -12 -6 0 6 12 18 24 30 36 42 48 (0.12 to 0.61) 0.28) 1.46)
Mos From Switch

Mallon. AIDS 2020. Abstr OAB0604. Slide credit: clinicaloptions.com

 OPERA: Weight Change With Switch From TDF to TAF
While Also Switching to an INSTI
Estimated Weight
Δ by Time From EVG/c DTG BIC
92 TDF to TAF Switch, (n = 1120) (n = 174) (n = 129)
90 kg/yr (95% CI)
88 DTG
0.22 0.01
EVG/c -60 to 0 mos 0.24 (-0.08 to (-0.38 to
Weight (kg)

86 (0.04 to 0.43)
84
0.52) 0.39)
BIC
82 2.55 3.09 4.47
0 to 9 mos
80 (1.86 to 3.24) (1.26 to 4.93) (0.81 to 8.13)
78 0.26 -0.23 -9.97
9+ mos (-0.10 to (-1.62 to (-23.79 to
0 0.61) 1.16) 3.85)
-60 -54 -48 -42 -36-30-24-18 -12 -6 0 6 12 18 24 30 36 42 48
Mos From Switch

Mallon. AIDS 2020. Abstr OAB0604. Slide credit: clinicaloptions.com

 TANGO: Metabolic Changes With Switch From
3- or 4-Drug TAF-Based ART to 2-Drug DTG/3TC
 Randomized, open-label phase III noninferiority study of switch to DTG/3TC vs continued
TAF-based 3- or 4-drug ART in virologically suppressed adults
‒ Weight gain of +0.81 kg with switch to DTG/3TC vs +0.76 kg with continued TAF-based
ART at Wk 48
Overall Boosted Subgroup Unboosted Subgroup
Metabolic Parameter, % TAF-Based P TAF-Based P TAF-Based P
DTG/3TC DTG/3TC DTG/3TC
ART Value ART Value ART Value
Change from BL to Wk 48
 Median A1C 5.3 5.4 NS - - - - - -
 Mean fasting glucose - - - 2.3 3.8 NS -0.2 2.1 NS
HOMA-IR* ≥ 2 at Wk 48 65 74 - 64 76 - 67 69 -
Metabolic syndrome at 11 12 - 10 9 - 14 24 -
Wk 48
*HOMA-IR = fasting plasma insulin (mU/L) x fasting plasma glucose (mmol/L); method for assessing β-cell function and insulin resistance with
levels > 1.9 indicating early insulin resistance.

van Wyk. AIDS 2020. Abstr OAB0606. Slide credit: clinicaloptions.com

 TANGO: Odds Ratios for HOMA-IR ≥ 2 and
Metabolic Syndrome at Wk 48
Favors TAF- Favors TAF-
Favors DTG/3TC Favors DTG/3TC
based regimen based regimen
Overall P = .008
0.59 Boosted
1.24
Boosted P = .012
0.56
Unboosted
Unboosted 0.41
0.70
0.1 1 10 0.1 1 10
Adjusted OR for HOMA-IR ≥ 2 (95% CI)* Adjusted OR for Metabolic Syndrome (95% CI)†
*Overall population adjusted for treatment, baseline third agent class, CD4+ cell count, age, sex, race, baseline BMI, baseline HTN, baseline smoking status, log-transformed
baseline HOMA-IR, and treatment-by-baseline third class agent interaction. Boosted and unboosted subgroups adjusted for treatment regimen, baseline boosting status, race,
sex, baseline BMI, baseline CD4+ cell count, age, baseline HTN, log-transformed baseline HOMA-IR, and treatment-by-baseline boosting status interaction. †Adjusted for
treatment regimen, baseline boosting status, sex, baseline HTN, baseline triglycerides, baseline HDL, baseline HOMA-IR, and treatment-by-baseline boosting status interaction.

van Wyk. AIDS 2020. Abstr OAB0606. Slide credit: clinicaloptions.com

 TANGO: Lipids Changes From BL to Wk 48 With Switch
From 3- or 4-Drug TAF-Based ART to 2-Drug DTG/3TC
Overall Boosted Subgroup Unboosted Subgroup
Change
From BL to TAF-Based TAF-Based TAF-Based
DTG/3TC P DTG/3TC P DTG/3TC P
Wk 48, % (n = 275) ART Value (n = 202) ART Value (n = 97) ART Value
(n = 263) (n = 203) (n = 94)
Total -4.5 2.3 < .001 -5.7 2.2 < .001 -0.8 2.0 --
cholesterol

HDL -1.2 1.7 -- -0.8 1.02 -- -2.3 0.1 --

LDL -5.5 2.2 < .001 -6.6 2.9 < .001 -2.0 -0.3 --

Triglycerides -11.2 6.0 < .001 -14.1 4.0 < .001 -1.6 12.2 --

TC:HDL ratio -3.3 0.5 .017 -4.8 0.1 .007 1.4 1.8 --

van Wyk. AIDS 2020. Abstr OAB0606. Slide credit: clinicaloptions.com

 DRIVE-SHIFT: Study Design
 International, randomized, open-label phase III noninferiority study[1,2]
Base Study Extension Phase
Wk 24 Wk 48 Wk 144

Adults with HIV-1 RNA

< 40 c/mL, stable ART DOR/3TC/TDF* DOR/3TC/TDF*
DOR/3TC/TDF*
for ≥ 6 mos, and eGFR (n = 447) (n = 427)
≥ 50 mL/min; no prior
Baseline ART† DOR/3TC/TDF*
VF or resistance to DOR/3TC/TDF*
(n = 223) (n = 209)
study drugs
(N = 670) *DOR/3TC/TDF dosing: 100/300/300 mg QD.
†
2 NRTIs + boosted PI (ATV, DRV, or LPV), EVG/COBI, or NNRTI (EFV, NVP, or RPV).

 Post-hoc analysis: weight changes and BMI changes analyzed separately for patients
immediately switching to DOR/3TC/TDF at Wk 0 vs delaying switch to Wk 24

1. Kumar. AIDS 2020. Abstr OAB0605. 2. Johnson. JAIDS. 2019;81:463. Slide credit: clinicaloptions.com
 DRIVE-SHIFT: Post-Switch Mean Weight Change
2.5 Immediate Switch
2.0
Mean Weight Immediate Delayed
Δ,* kg (95% CI) Switch Switch
1.5
Mean Weight Δ,* kg (95% CI)

1.0
Wk 24 0.7 NA
0.5 (0.4-0.9)
0.0
Wk 48 0.7 0.5
-0.5 (0.4-1.1) (0-1.0)
2.5
Delayed Switch 1.1 0.8
2.0 Wk 96
1.5 (0.7-1.6) (0.2-1.5)
1.0 1.4 1.2
0.5 Wk 144
(0.8-1.9) (0.4-2.0)
0.0
-0.5
0 4 12 2428 36 48 64 80 96 112 128 144
Wk
*Adjusted for weight at switch, race (black vs nonblack), ethnicity (Hispanic vs other), sex, age, BL CD4+ cell count, and HIV-1 RNA.

Kumar. AIDS 2020. Abstr OAB0605. Slide credit: clinicaloptions.com

 DRIVE-SHIFT: Post-Switch BMI Change and Percent
Weight Change
 80.2% to 95.5% of patients with a normal, overweight, or obese BMI at the time of switch maintained
their respective BMI categories at Wk 144
 50% of underweight patients in the immediate switch arm shifted to a normal BMI category at Wk 144;
all underweight patients in the delayed switch arm maintained an underweight BMI at Wk 144
Weight Gain ≤ 0% > 0% to < 5% 5% to < 10% ≥ 10%
24 Wks Post Switch Wk 144*
100 2.6 2.5 100
8.4 8.4 7.9
9.4
80 80 17.9 20.3
Participants (%)

Participants (%)
44.3 39.6
60 60 29.9
33.3
40 40

20 43.8 49.5 20 43.9 38.4

0 0
Immediate Switch Delayed Switch Immediate Switch Delayed Switch
*144 wks (~ 2.8 yrs) from switch in immediate switch arm vs 120 wks (~ 2.3 yrs) from switch in delayed switch arm.
Kumar. AIDS 2020. Abstr OAB0605. Slide credit: clinicaloptions.com
 Additional Data on Weight Gain and ART From AIDS 2020
Study Population Reported Outcome
Adults with HIV infection starting 1.85 times the rate of developing high BMI with
or switching ART at 12 PEPFAR DTG/3TC/TDF vs other ART; no significant
AFRICOS[1] supported clinics in Uganda, difference in hyperglycemia incidence with
Kenya, Tanzania, and Nigeria
DTG/3TC/TDF vs other ART
(N = 2927)
Virologically suppressed adults
Pooled ≥ 65 yrs of age randomized to
analysis of switch to BIC/FTC/TAF in Study Median weight gain of +1.0 kg (IQR: -0.9 to 3.0)
switch to 380-1844, Study 380-4030, at Wk 48
BIC/FTC/TAF[2] Study 380-4449, and Study 380-
1878 (N = 140)

1. Ake. AIDS 2020. Abstr OAB0602. 2. Ramgopol. AIDS 2020. Abstr OAB0403. Slide credit: clinicaloptions.com
 Retrospective Cohort Study of Cardiac Events Among
PWH Receiving TAF
Unadjusted Kaplan-Meier Cardiac Event-Free Survival TAF TDF No TFV
Cardiac Event, n
(n = 1537) (n = 1170) (n = 278)
TAF MI 8 23 4
1.00
TDF Angina pectoris 13 15 5
No TFV
Cardiomyopathy 6 3 1
Cumulative Survival

0.95 Arrhythmia 16 17 1
Total 43 58 11
0.90 Risk of Cardiac Adjusted HR
P Value
Event (95% CI)
TAF vs no TFV 3.86 (1.51-9.82) .005
0.85
0 10 20 30 TAF vs TDF 1.94 (1.05-3.57) .034
Yrs After Start Date

Appelman. CROI 2020. Abstr 655. Slide credit: clinicaloptions.com

 DHHS Guidelines: Weight Gain and ART
 New guidelines recognize weight gain as a common and/or severe AE associated with
ART
“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.”

 Currently no recommendation to avoid INSTIs or TAF due to potential for weight gain
 Further studies are needed to better understand weight gain distribution, its
association with increased risk for cardiometabolic disease, and whether the weight
gain can be reversed with drug discontinuation
DHHS Guidelines. December 2019. Slide credit: clinicaloptions.com
Patient Case 1: Update
 ART regimen selection considerations
‒ Weight gain risk for a male with a normal BMI?
‒ Demographic risk factors?
 No recommendation to avoid INSTIs or TAF but clinicians should ensure appropriate
patient counseling
‒ Weight gain is expected for all treatment-naive PWH initiating ART, regardless of
treatment regimen
‒ It remains unclear whether the weight gained is a result of better drug efficacy or
off-target effects of treatment
‒ Patients should monitor weight and bring up an concerns to provider
Key Take-home Points
 Compared with EFV/FTC/TDF, the higher weight gain noted with DTG + FTC/TAF is
likely associated with increased risk for developing metabolic syndrome
 Switching from TDF to TAF based regimens is universally associated with rapid
weight gain, regardless of the other HIV drugs in the regimen
 Switching off TAF-based regimens to a 2-drug regimen of DTG/3TC appears to be
associated with decreased risk of insulin resistance and improvement in lipid profile
 Virologically suppressed adult PWH switching to DOR/3TC/TDF experience modest
amounts of weight gain
 Compared with TDF-containing and tenofovir free regimens, TAF-based regimens
have been associated with increased risk of cardiac events in early analyses

Slide credit: clinicaloptions.com

ART in Women of Childbearing Potential
Patient Case 2: Background
 24-yr-old woman recently tested positive Parameter at Current Value
for HIV Presentation
CD4+ cell count, cells/mm3 254*
‒ Last negative test was July 2019
HIV-1 RNA, copies/mL 367,000
 She is currently 10 wks pregnant with her HIV-1 genotype Wildtype
first child HLA-B*5701 Negative
 Nonsmoker, drinks alcohol occasionally, BMI 24
and has substance use disorder (injects HBV Immune
heroin) HCV antibody Negative

‒ Has been sober for more than 6 mos

*Other CBC parameters normal.
 Takes a perinatal vitamin
 “I want a treatment that is safe for me
and the baby”
 DHHS Recommendations Before Initiating an INSTI in
Person of Childbearing Potential
 A pregnancy test should be performed; DTG remains a preferred option in
pregnancy regardless of trimester[1,2]
 “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”[1]
Persons of Childbearing Potential Initiating ART[1]*
 Using effective contraception: DTG is a recommended option
 Sexually active, not planning to conceive, but not using contraception:
DTG is an alternative option
 Trying to conceive: initiate a regimen preferred during pregnancy; DTG is an
alternative option
*Consider an approach with BIC similar to that outlined for DTG.
1. DHHS Guidelines. December 2019. 2. DHHS Perinatal Guidelines. April 2020. Slide credit: clinicaloptions.com
 DHHS Recommendations on ART in Pregnancy
 “All pregnant women with HIV should initiate ART as early in pregnancy as
possible”
Preferred Regimens
INSTI
2 NRTIs  RAL BID Boosted PI
 ABC/3TC
 FTC/TDF +  DTG (preferred in pregnancy and OR  ATV/RTV
alternative in women trying to  DRV/RTV BID
 3TC/TDF
conceive)

Alternative Regimens Not Recommended

2 NRTIs  TAF, BIC, IBA, and DOR due to
 ABC/3TC NNRTIs insufficient data
 FTC/TDF +  EFV  EVG/COBI, ATV/COBI, and
 3TC/TDF  RPV DRV/COBI due to
pharmacokinetic concerns

DHHS Perinatal Guidelines. April 2020. Slide credit: clinicaloptions.com

 Tsepamo Birth Outcomes Surveillance Study in
Botswana: Background
 In May 2018, unplanned analysis of Tsepamo birth outcomes surveillance study found
increase in NTD incidence among Botswanan women who conceived on DTG[1]
‒ DTG vs non-DTG ART: 0.94% (95% CI: 0.37-2.4) vs 0.12% (95% CI: 0.07-0.21)
‒ Prevalence difference: 0.82% (95% CI: 0.24-2.3)

 Analysis of data through March 2019 found NTD prevalence among women who
received DTG at conception lower than previous analysis but still higher than other
exposure groups[2]
‒ DTG vs non-DTG ART: 0.30% (95% CI: 0.13-0.69) vs 0.10% (95% CI: 0.06-0.17)
‒ Prevalence difference: 0.20% (95% CI: 0.01-0.59)

 Most recent analysis reports data from Tsepamo through April 2020[3]

1. Zash. NEJM. 2018; 379:979. 2. Zash. IAS 2019. Abstr MOAX0105LB. 3. Zash. AIDS 2020. Abstr OAXLB0102. Slide credit: clinicaloptions.com
 Tsepamo Update: Prevalence of NTDs by ARV Exposure
Conception Pregnancy
HIV Negative
Parameter DTG Non-DTG EFV DTG (n = 119,630)
(n = 3591) (n = 19,361) (n = 10,958) (n = 4581)
Total NTDs per exposures, n/N 7/3591 21/19,361 8/10,958 2/4581 87/119,630
NTD prevalence, % (95% CI)
 March 2019 0.30 0.10 0.04 0.03 0.08
(0.13-0.69) (0.06-0.17) (0.01-0.11) (0.0-0.15) (0.06-0.10)
 April 2020 0.19 0.11 0.07 0.04 0.07
(0.09-0.40) (0.07-0.17) (0.03-0.17) (0.01-0.16) (0.06-0.09)

Prevalence diff. from DTG 0.09 0.12 0.15 0.12

Ref
conception, Apr 2020, % (95% CI) (-0.03 to 0.30) (0.0 to 0.32) (0.0 to 0.36) (0.01 to 32)
NTDs per exposures between
2/1908* 6/4569 5/2999 1/741 17/30,258
March 2019 and April 2020, n/N
*Includes 1 lumbosacral myelomeningocele (spina bifida) and 1 encephalocele.

Zash. AIDS 2020. Abstr OAXLB0102. Slide credit: clinicaloptions.com

 Predicted Risk of Adverse Pregnancy Outcomes From
Treatment-Induced Obesity in ADVANCE Trial
 Predicted 10-yr risk of adverse pregnancy outcomes in ADVANCE; combined treatment-emergent
obesity at Wk 96 with relative risks for obese vs normal weight pregnant women determined by
systematic review
Adverse Adverse
Outcomes per DTG/ DTG/ EFV/ Outcomes per DTG/ DTG/ EFV/
BL FTC/TAF FTC/TDF FTC/TDF BL FTC/TAF FTC/TDF FTC/TDF
1000 Pregnancies 96 Wks 96 Wks 96 Wks 1000 Pregnancies 96 Wks 96 Wks 96 Wks
(Δ From BL) (Δ From BL)
Preterm delivery 70 73 (+3) 71 (+1) 70 (0) Small for
89 87 (-2) 88 (-1) 89 (0)
gestational age
Gestational HTN 28 39 (+11) 34 (+6) 29 (+1)
Gestational Large for 134 154 145 (+11) 137 (+3)
16 23 (+7) 19 (+3) 16 (0) gestational age (+20)
diabetes
Pre-eclampsia 25 35 (+10) 30 (+5) 26 (+1) Macrosomia 31 37 (+6) 34 (+3) 31 (0)
Neonatal death 2 2 (0) 2 (0) 2 (0)
Postpartum
112 115 (+3) 114 (+2) 112 (0)
hemorrhage NTD 0 0 (0) 0 (0) 0 (0)
Caesarean section 213 232 (+19) 224 (+11) 215 (+2) Total effect +24 +13 +3
Stillbirth 4 4 (0) 4 (0) 4 (0)

Asif. AIDS 2020. Abstr OABLB0103. Slide credit: clinicaloptions.com

 Adverse Pregnancy Outcomes With DTG vs EFV:
Meta-analysis of 5 Clinical Trials
 Meta-analysis of 5 recent trials that have included pregnant women: DolPHIN-1,
DolPHIN-2, NAMSAL, ADVANCE, and IMPAACT 2010 (N = 1074)
P = .001 DTG-based ART EFV-based ART
100
90%
80 72%
Participants (%)

60
P = .06
40 P = .73
28%
22% 22%
P = .06 P = .68 P = .18 18%
20
4% 2% 2% 3% 1% 0%
0 Viral Suppression Stillbirth Neonatal Deaths MTCT Mothers With ≥ 1 AE Infants With ≥ 1 AE
n/N = 547/605, 271/378 26/659, 9/415 10/659, 12/415 5/659, 0/415 141/649, 73/403 130/590, 105/370
Outcome
Asif. AIDS 2020. Abstr OABLB0105. Slide credit: clinicaloptions.com
Patient Case 2: Update
 ART regimen selection considerations for this patient:
‒ DTG preferred over EFV
‒ Faster viral suppression
‒ Well tolerated with high barrier for resistance
‒ NTD risk appears lower than previously described (and statistically not
different from EFV)
‒ However, we still need long-term safety analysis of DTG and its association
with weight gain, especially among pregnant black women
 Bone Loss With DMPA Contraception in Young Women
Initiating TDF-Containing ART
 Study of women aged 18-35 yrs from Kampala, Uganda, initiating TDF-containing ART with or without
concomitant DMPA use compared with women without HIV not using DMPA (N = 334)
 In women initiating TDF-containing ART, DMPA use associated with ~ 2 x greater loss in BMD vs those
not using DMPA (mean annualized change in BMD: -2.1% to -2.5% vs -0.8% to -1.1%, respectively)
HIV+/DMPA+/TDF+ HIV+/DMPA-/TDF+ HIV-/DMPA-/TDF-
Lumbar Spine BMD Total Hip BMD Femur Neck BMD
2 2 2
1 1 1
Mean Δ (%)

Mean Δ (%)

Mean Δ (%)
0 P < .001 0 0
-1 -1 P < .001 -1 P < .001
-2 -2 -2
-3 -3 -3
-4 -4 -4
-5 -5 -5
0 6 12 18 24 0 6 12 18 24 0 6 12 18 24
Mos Mos Mos
*Pair-wise comparison adjusted for age, BMI, and baseline BMD.

Matovu. AIDS 2020. Abstr OAB0105. Slide credit: clinicaloptions.com

Key Take-home Points
 The prevalence of NTD among women with HIV receiving DTG at time of
conception is lower than that previously reported, and no longer
statistically significan
 Treatment-related obesity may increase the risk of adverse pregnancy
outcomes
 The faster virologic suppression with DTG vs EFV does not appear to
lower the risk of HIV MTCT
 Although bone loss with TDF is well documented, the degree of bone loss
is significantly worse among young women who are also on DMPA
contraception
Slide credit: clinicaloptions.com
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