Современное лечение ВИЧ: модификация АРТ у пациентов с вирусологической супрессией (2021) / Contemporary Management of HIV: Modifying ART in Virologically Suppressed Patients 2021

Contemporary Management of HIV:
Modifying ART in Virologically Suppressed
Patients
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
Paul E. Sax, MD, has disclosed disclosed that he has received consulting fees
from Gilead Sciences, GSK/ViiV Healthcare, Janssen, and Merck and funds for
research support from Gilead Sciences, GSK/ViiV Healthcare, and Merck.
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.

Program Overview
 Case-Based Discussion: Modifying ART in Virologically Suppressed
Patients
‒ Switching ART in a Patient With Daily Pill Fatigue
‒ Switching ART to Avoid Comorbidities
‒ Simplifying ART in the Context of Known Multidrug Resistance
 Question and Answer Session

Switching ART in a Patient With
Daily Pill Fatigue

Patient Case 1: Background
 39-yr-old MSM diagnosed with HIV
in 2015 shortly after being found unconscious
on the street and brought to hospital by police
 Urine toxicology screen positive for cocaine,
alcohol, and amphetamines
 When he awoke, he acknowledged
polysubstance use and selling sex for money
 Agreed to HIV testing, which was positive
 Laboratory parameters at HIV diagnosis:
‒ CD4+ cell count: 334 cells/mm3
‒ HIV-1 RNA: 34,000 copies/mL
‒ No HIV drug resistance
‒ Hepatitis serologies negative, including HAV,
HBV, HCV
 Started on EVG/COBI/FTC/TAF, one pill daily
and rapidly achieved viral suppression
 Transferred to an inpatient substance use
disorder treatment program, has been in
recovery since then, with excellent
medication adherence
 No other medical problems except for
intermittent STIs, diagnosed on routine
screens
 Expresses that he’s tired of taking a daily pill
for HIV – reminds him of the time of his
diagnosis and difficulties with addiction

Reasons to Consider an ART Switch During Viral
Suppression
Appropriate
 To simplify a regimen (eg, reduce pill
burden or dosing frequency)
 To enhance tolerability or decrease
toxicity
 To prevent or mitigate drug–drug or
drug–food interactions
 To eliminate food/fluid requirements
 To allow for optimal ART use during
pregnancy or where pregnancy may occur
 To reduce costs
Inappropriate
 To use the “newest” regimen
 To reduce costs at the price of a toxicity
or intolerance risk for your patient
DHHS Guidelines. December 2019.

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 + LA 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 +
LA 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 Endpoint
Wk 4
DTG/ABC/3TC PO QD
Wk 96
Day 0
Wk 20
FLAIR
1. Swindells. NEJM. 2020;382:1112. 2. Orkin. NEJM. 2020;382:1124.
CAB 30 mg +
RPV 25 mg PO QD
(n = 308)
Wk 4
Day 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)*
Key Secondary Endpoint
(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 ART
LA 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/3TC
LA 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. Orkin. CROI 2020. Abstr 482LB.
• Noninferiority also observed at Wk 96
• No additional CVF during Wk 48 to 96 in CAB+RPV arm

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
‒ At Wk 96, no additional cases of treatment-emergent resistance
1. Swindells. CROI 2019. Abstr 139. 2. Orkin. CROI 2019. Abstr 140LB. 3. Overton. IAS 2019. Abstr MOPEB257. Orkin. CROI 2020. Abstr 482LB. 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) --

Long-Acting CAB + RPV Approved by FDA January 21,
2021
 FDA indication:
‒ As complete regimen for HIV-1 infection treatment switch in adults who
are virologically suppressed on a stable ART regimen
‒ No history of treatment failure and no known or suspected resistance to
either CAB or RPV
 Requires oral CAB + RVP lead-in dosing for ~ 1 mo to assess tolerability
 Initiate IM gluteal injection of CAB 600 mg + RPV 900 mg on last day of
oral lead-in period and continue injections every mo thereafter
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/212888s000lbl.pdf. Slide credit: clinicaloptions.com

Questions to Consider
 Which of your patients will be good candidates for this novel
treatment?
 How would you counsel them about the pros and cons?
 What concerns do you have?

Case Report: Acute Hepatitis B in a Patient on CAB/RPV
 31-yr-old MSM diagnosed with HIV 11/16; started induction ART in 2/17 with DTG, 3TC, and ABC in
FLAIR study; no markers of prior HBV infection, no history of HBV vaccination at screening
‒ 4/17: HIV-1 plasma viral load undetectable
 9/17: randomized to 4-wk oral CAB/RPV, followed by monthly LA CAB/RPV injection
 HBV vaccine and HAV vaccine: 7/17, 8/17, 4/18; treated 12/16 and 4/18 for syphilis, urethral and
anal chlamydia, and shigellosis
 6/18: increased AST (78 IU/L) and ALT (162 IU/L); continued increase in ALT to 594 IU/L
‒ Diagnosis acute HBV infection: HBsAg+, HBsAb-, HBc IgM+, HBeAg+, HBeAb-, high HBV DNA level of
229,000,000 IU/mL (8.36 log10)
 Retrospective testing of 1/18 serum found no detectable anti-HBsAb
 7/18: switched to TDF,FTC, and DTG; after 3 mos, normal ALT, decreased HBV DNA level to 170
IU/mL (2.23 log10)
Pintado. Open Forum Infect Dis. 2020;7:ofaa367.

Factors That May Contribute to Risk of Treatment
Failure With Long-Acting CAB/RPV
 Post-hoc analysis of phase III data (Wk 48)
‒ ATLAS and FLAIR (Q4W dosing)
‒ ATLAS-2M (Q4W and Q8W dosing)
 Logistic regression model (10 covariates)
 Factors associated with increased odds of
confirmed virologic failure:
‒ Rilpivirine RAMs at baseline: OR 37.2 (P < .001)
‒ Log2 of post-hoc Wk 8 rilpivirine trough
concentration: OR 4.2 (P = .004)
‒ Baseline HIV-1 subtype A1/A6: OR 6.6 (P =
.005)
‒ BMI ≥ 30 kg/m2 at baseline: OR 1.1 (P = .001)
 Q8W dosing was not a significant factor
Margolis. J Int AIDS Soc. 2020;23(suppl 7):17. Wensing. Top Antivir Med. 2019;27(3):111-121.
Baseline
Factors
Confirmed Virologic
Failure (%)
HIV-1 RNA < 50
Copies/mL (%)
None 0.4 95
1 0.4 96
≥ 2 26 71
Total 1.3 94
E138K
V90I
K101E/P/T
V179I/D/L
Y181C/I/V
V189I
H221Y
F227C/L
M230I/L
Rilpivirine RAMs

“Direct to Inject”: Switching to CAB/RPV Without an
Oral Lead-In
 FLAIR extension study
‒ Participants on DTG/ABC/3TC
arm achieving virologic
suppression (HIV-1 RNA < 50
copies/mL) in 20-wk induction
phase could switch to monthly
CAB/RPV at Wk 100
‒ Switchers randomized to groups
with (n = 121) or without (n =
111) an oral CAB + RPV lead-in
D’Amico. J Int AIDS Soc. 2020;23(suppl 7):15.
Patients
(%)
99.1
93.4
0.9 0.8 0
5.8
Virologic Outcomes at Wk 124 Following
Switch to CAB/RPV at Wk 100
No lead-in
Lead-in
Virologic
Nonresponse
Virologic
Suppression
No Virologic
Data
100
80
40
60
20
0

Questions for Discussion
 Would you still consider injectable CAB/RPV for the case patient if …
‒ He had a history of treatment interruptions?
‒ He had transmitted K103N (resistance to efavirenz)?
‒ This was a woman of childbearing potential?
‒ This was a time with a COVID-19 surge?
‒ If he was a frequent traveler who spent wks at a time out of the country?
‒ He was not HBV immune?
‒ His baseline (pre-therapy) genotype was not available

Switching ART to Avoid Comorbidities

 66-yr-old woman diagnosed with HIV in
2008 when her husband was hospitalized
with PJP
 Her initial CD4+ cell count was 480
cells/mm3, HIV-1 RNA 67,000 copies/mL,
with no transmitted resistance
 Started EFV/FTC/TDF, later switched to
ATV/RTV + FTC/TDF because of CNS
adverse effects
 Ended up on DRV/RTV + FTC/TDF because
she needed to take acid-reducing
medication for reflux
 Switched to single pill DRV/COBI/FTC/TAF
in 2019, which she tolerates well
 Additional medical history
‒ HTN
‒ Type 2 DM
‒ Renal impairment (eGFR 45
mL/min/1.73m2)
‒ Obesity
 Current other medications: atorvastatin,
amlodipine, valsartan, metformin,
pantoprazole
 Nonsmoker
 Strong family history of cardiac disease

Considerations When Switching Regimens in Virologically
Suppressed Patients
Comorbidity:
 HBV coinfection
 Cardiovascular disease or risk
 Renal function
 Bone mineral density
 Pregnancy
 Other coinfections
Safety:
 Review ART history for intolerance
 Must be HLA-B*5701 negative if considering ABC
 Consider drug–drug interactions with
comedications
Drug Resistance:
 Review ART history for possible VF
 Review all available resistance test results
 If earlier resistance uncertain, only consider
switch if new regimen likely to maintain
suppression of resistant virus
 Within-class switches usually maintain virologic
suppression if no resistance to drugs in that class
are present
 Caution when switching from boosted PI to
another class if full treatment/resistance history
not known
 Consult an expert when switching if resistance to
≥ 1 class
DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com

Data Collection on Adverse Events of Anti-HIV Drugs
(D:A:D) Study: DRV Associated With Increased CVD Risk
 Prospective, multinational analysis
previously showed that longer,
cumulative use of older PIs IDV and
LPV/RTV associated with CVD risk[1]
 Adequate data available for 35,711
participants; during mean follow-up of ~ 7
yrs, 1157 developed CVD[1]
‒ 379 stroke
‒ 454 type 1 myocardial infarction
‒ 459 angioplasty
‒ 93 bypass
‒ 15 endarterectomy
‒ 0 sudden cardiac deaths
*After adjustment for potential confounders.
1. Ryom. Lancet HIV. 2018;5:e291. 2. Saag. JAMA. 2020;324:1651.
 Cumulative use of RTV-boosted DRV, but
not RTV-boosted ATV, was independently
associated with small, but progressively
increasing risk of CVD events[1]
 IAS-USA ART guidelines recommend
switching from ABC-based or PI-
containing regimens (except ATV) in
patients with or at high for CVD event[2]
Regimen[1] Incidence Rate Ratio/5 Yrs*
(95% CI)
RTV-boosted DRV 1.59 (1.33-1.91)
RTV-boosted ATV 1.03 (0.90-1.18)

Switching From Suppressive ART to an STR:
Noninferior Efficacy Across Phase III Studies
1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Sax. IAS 2019. Abstr MOAB0105. 4. Kityo. CROI 2018. Abstr 500. 5.
Johnson. JAIDS. 2019;81:463. 6. Orkin. Lancet HIV. 2017;4:e195. 7. DeJesus. Lancet HIV. 2017;4:e205. 8. Trottier. Antivir Ther. 2017;22:295.
9. Mills. Lancet Infect Dis. 2016;16:43. 10. Orkin. Lancet HIV. 2018;5:e23 11. van Wyk. Clin Infect Dis. 2020;71:1920. 12. Llibre. Lancet.
2018;391:839. 13. Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com
Key Studies* Switch to† Switch From
380-1878,[1] 380-1844,[2] 380-4030‡,[3] 380-
1961,‡[4] and BRAAVE‡[13] BIC/FTC/TAF
Boosted PI + 2 NRTIs, DTG/ABC/3TC, DTG +
FTC/(TAF or TDF), or EVG/COBI/FTC/(TAF or TDF),
2 NRTIs + third agent
DRIVE-SHIFT[5] DOR/3TC/TDF Boosted PI, EVG/COBI, or NNRTI + 2 NRTIs
GS-1216[6] and GS-1160[7] RPV/FTC/TAF RPV/FTC/TDF or EFV/FTC/TDF
STRIIVING[8] DTG/ABC/3TC Third agent + 2 NRTIs
GS-109[9] EVG/COBI/FTC/TAF TDF-based regimen
EMERALD‡[10] DRV/COBI/FTC/TAF Boosted PI + FTC/TDF
TANGO[11] DTG/3TC 3-drug or 4-drug TAF-based ART
SWORD-1/2[12] DTG + RPV Third agent + 2 NRTIs
*Listed studies not head to head. †Most recent FDA approvals: for BIC/FTC/TAF, DTG/RPV, DOR/3TC/TDF, and DTG/3TC must have no history of
treatment failure and no resistance to regimen components; for DRV/COBI/FTC/TAF, must have no resistance to DRV, TFV. ‡Patients with
resistance permitted.

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 in adults on stable ART (INSTI,
NNRTI, or PI + 2 NRTIs) with HIV-1 RNA < 50 copies/mL for ≥ 6 mos[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[1]
‒ Treatment-emergent NNRTI resistance mutations documented in 3/10, all from early switch arm*
Time of
Failure
Previous
Regimen
Mutations at Baseline
Mutations at
Confirmed Virologic Withdrawal
NNRTI INSTI NNRTI INSTI
Wk 36 EFV/FTC/TDF None None K101K/E None
Wk 88 DTG/ABC/3TC None None E138E/A None
Wk 100 EFV/FTC/TDF K101E, E138A G193E
K101E, E138A,
M230M/L
Assay failure
*For these 3 patients, HIV-1 RNA at last measurement: < 50 copies/mL, 55 copies/mL, 300 copies/mL, respectively.
1. Aboud. AIDS 2018. Abstr THPEB047. 2. Llibre. Lancet. 2018;391:839.

Comorbidity, n (%)
Treatment Experienced
Suppressed
(n = 671)
Not Suppressed
(n = 197)
Any 587 (87.5) 159 (80.7)
Autoimmune disease 29 (4.3) 8 (4.1)
Cardiovascular disease 89 (13.3) 20 (10.2)
Invasive cancer 80 (11.9) 15 (7.6)
Endocrine disorder 422 (62.9) 94 (47.7)
Mental health disorder 232 (34.6) 58 (29.4)
Liver disease 115 (17.1) 40 (20.3)
Bone disorder 52 (7.7) 17 (8.6)
Peripheral neuropathy 83 (12.4) 27 (13.7)
Renal disease 198 (29.5) 51 (25.9)
Hypertension 290 (43.2) 77 (39.1)
Substance use 92 (13.7) 31 (15.7)
Real-World Experience With DTG/RPV in the
United States
 Retrospective analysis of clinical characteristics and
outcomes in PWH switching to DTG/RPV between
Jan 2018 and Dec 2018 in OPERA study (N = 880)
 BL characteristics: 68% had CD4+ cell count
> 500 cells/mm3, 63% initiated ART after 2013
 88% remained on drug at 12 mos, virologic failure
occurred in 1.5%; 12% (n = 42) discontinued, of
whom 41% were virologically suppressed
Pierone. IDWeek 2019. Abstr 2483. Slide credit: clinicaloptions.com
Region (South)
Age (50+)
Risk Factor (MSM)
Race (Black)
Ethnicity (Hispanic)
Sex (Female)
0 10 20 30 40 50 60 70 80 90 100
Baseline Demographics of Patients Switching to DTG/RPV (N = 880)
DTG/RPV switch
Overall OPERA
population
63%
57%
54%
38%
35%
60%
35%
44%
28%
25%
18%
17%

Rilpivirine and Acid-reducing Therapies
Agent Effect on RPV Concentration Clinical Comment
Antacids: aluminum or magnesium
hydroxide, calcium carbonate
No change if antacid taken ≥ 2 hrs
before RPV or ≥ 4 hrs after RPV
Use antacid + RPV with caution; may
cause decreases in RPV plasma
concentration
H2-receptor antagonists: cimetidine,
famotidine*, nizatidine, ranitidine
No change if famotidine taken ≥ 12
hrs before RPV or ≥ 4 hrs after RPV;
decreased RPV if famotidine taken 2
hrs before RPV
Use H2-receptor antagonists + RPV
with caution; may cause decreases in
RPV plasma concentration
Proton pump inhibitors:
esomeprazole, lansoprazole,
omeprazole, pantoprazole,
rabeprazole
Decreases in RPV
plasma concentrations may occur
due to gastric pH increase
Do not coadminister proton pump
inhibitors with RPV
1. Rilpivirine PI. 2. Crauwels. J Int AIDS Soc. 2008;11(Suppl1:239). Slide credit: clinicaloptions.com
*RPV-famotidine interaction assessed in a clinical study.[2]

Switch from Boosted PIs to BIC/FTC/TAF
Daar. Lancet HIV. 2018;5:e347.
 Multicenter, randomized, open-label, active-controlled, phase III noninferiority trial
BIC/FTC/TAF
(n = 290)
Continue Baseline Boosted PI
(n = 287)
Adults with HIV-1 infection with
eGFR ≥ 50 mL, plasma HIV-1
RNA < 50 copies/mL ≥ 6 mos; on
regimen of boosted PI* (N =
578; 1 randomized participant
was not treated)
*ATV or DRV + FTC/TDF or 3TC/ABC.
Wk 48 Primary
Endpoint
 Primary endpoint: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA snapshot algorithm with 4%
prespecified noninferiority margin
 Result: HIV-1 RNA ≥ 50 copies/mL at Wk 48: 2% with BIC/FTC/TAF or continued boosted PI
Stratified by use of TDF or ABC
at screening

(HIV-1 RNA < 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
TANGO: Switch to DTG/3TC vs Continuing TAF-Based
3-Drug Regimen
0.5
Patients
(%)
100
80
40
60
20
0
HIV-1 RNA
≥ 50 c/mL
HIV-1 RNA
< 50 c/mL
No Virologic
Data
0.3
93.2 93.0
6.5 6.5
Switch to DTG/3TC
(n = 369)
Continue TAF-based ART
(n = 372)
Virologic Outcomes by FDA Snapshot (ITT-E) at Wk 48 Adjusted Treatment Difference (95% CI)*
Primary Endpoint
(HIV-1 RNA ≥ 50 c/mL)
DTG/3TC noninferior to
continued TAF-based ART
*Adjusted for baseline third agent class.
Difference (%)
-3.4
0.2
-8 -6 -4 -2 0 2 4 6 8
3.9
-8% NI
margin
TAF-Based ART
DTG/3TC
TAF-Based ART DTG/3TC
-1.2 0.7
-0.3
-8 -6 -4 -2 0 2 4 6 8
4% NI
margin
van Wyk. IAS 2019. Abstr WEAB0403LB.
 No CVW in DTG/3TC arm, CVW in 1 (< 1%) patient in
TAF-based ART arm; no resistance detected at failure
 All 7 patients (4 in DTG/3TC group, 3 in TAF-based ART
group) with proviral M184V/I mutation at baseline
maintained HIV-1 RNA < 50 c/mL at Wk 48
 International, randomized, open-label phase III noninferiority study in adults with HIV-1 RNA < 50 c/mL for > 6
mos on TAF-based ART

TANGO: Lipid Changes at Wk 48
 In analysis excluding those with BL lipid-modifying agent use, lipid
changes favored switch to DTG/3TC (n = 275) vs continued TAF-based
ART (n = 263) in overall population
‒ Significant reductions in total cholesterol, LDL, triglycerides, and TC:HDL
ratio with DTG/3TC
 When stratified by previous use of boosting agents, statistically
favorable changes with DTG/3TC vs TAF-based ART persisted in
boosted subgroup
‒ Significant reductions in total cholesterol, LDL, triglycerides, and TC:HDL
ratio with DTG/3TC
van Wyk. Clin Infect Dis. 2020;71:1920. van Wyk. AIDS 2020. Abstr OAB0606.

TANGO: HbA1c, Fasting Glucose, and Fasting Insulin
Changes at Wk 48
 A1C and fasting glucose changes minimal, comparable between treatment arms;
fasting insulin changes statistically favored switch to DTG/3TC vs continued
TAF-based ART in boosted subgroup (P = .006), with trend for unboosted subgroup
van Wyk. AIDS 2020. Abstr OAB0606.
Metabolic Parameter, % DTG/3TC TAF-Based ART
Median change from BL in A1C 5.3 5.4
Adjusted mean change from BL in fasting glucose*
 Boosted baseline regimen
 Unboosted baseline regimen
2.3
-0.2
3.8
2.1
Adjusted mean change from BL in fasting insulin†
-11.7
-7.2
0.9
5.1
*DTG/3TC (boosted, n = 222; unboosted, n = 82); TAF-based ART (boosted, n = 221; unboosted, n = 60).
†DTG/3TC (boosted, n = 222; unboosted, n = 83); TAF-based ART (boosted, n = 218; unboosted, n = 61).

TANGO: Weight Change at Wk 48
 Overall weight gains minimal, comparable between treatment arms
van Wyk. AIDS 2020. Abstr OAB0606.
Weight Parameter
DTG/3TC
(n = 343)
TAF-Based ART
(n = 343)
Adjusted mean weight change from BL, kg (SE)
 Prior TAF duration < 1 yr*
 Prior TAF duration ≥ 1 yr†
0.81 (0.23)
1.45 (0.46)
0.60 (0.26)
0.81 (0.27)
0.81 (0.45)
0.76 (0.22)
1.35 (0.47)
0.60 (0.25)
0.88 (0.25)
0.40 (0.44)
Weight increase ≥ 10% from BL, n (%) 11 (3) 13 (4)
*DTG/3TC, n = 83; TAF-based ART, n = 76. †DTG/3TC, n = 260; TAF-based ART, n = 267.

The Do IT Study: Doravirine in PWH With Significant
Weight Gain on INSTIs + TAF
 ACTG 5391: randomized, open-label phase IV trial
 Primary endpoint: Differences in weight change over 48 wks
 Secondary endpoints: metabolic outcomes, viral load, safety
Overweight/obese (BMI ≥ 27.5
kg/m2) patients on RAL, DTG, or
BIC + FTC/TAF (or 3TC/TAF) with
unintentional > 10% weight gain
over prior 1-3 yrs
(N = 222) Continuation of entry INSTI + FTC/TAF (or
3TC/TAF)
Wk 48
DOR 100 mg QD +
FTC/TAF (or 3TC/TAF)
DOR 100 mg QD +
FTC/TDF (or 3TC/TDF)
NCT04636437. Slide credit: clinicaloptions.com

Safety of Full-Dose Lamivudine in Patients with eGFR <
50 mL/min
 Primary end points: mean model-simulated 3TC AUC (0–24 hr) and mean observed 3TC
concentrations predose (Cmin) and 0.5-1.5 hours postdose (Cmax)
 Observed 3TC Cmax values comparable across CrCl cohorts; simulated 3TC AUC values in participants
with impaired renal function consistent with historical data
 Lactic acid levels all within normal limits; no adverse effects
Men and nonpregnant,
nonlactating women age
≥ 18 yrs with HIV
receiving 3TC for ≥ 3 mos
(N = 34)
CrCl > 50 mL/min; 3TC 300 mg daily
(n = 5)
CrCl 30-49 mL/min; 3TC 300 mg daily
(n = 16)
Stratified by renal function
CrCl 15-29 mL/min; 3TC 150 mg daily
(n = 4; 1 on dialysis)
Hemodialysis; 3TC 100 mg or 150 mg daily
(n = 10)
Fischetti. Open Forum Infect Dis. 2018;5:ofy225.

Simplifying ART in the Context of
Known Multidrug Resistance

 60-yr-old man diagnosed with HIV
in 1990 when he experienced weight loss,
thrush, and dysphagia
 Treated with fluconazole and improved
rapidly; no HIV-related complications since
then
 Initial CD4+ cell count: 110 cells/mm3
 Treated with NRTIs (ZDV, ddI, d4T, 3TC)
until 1996, when he began various
combination regimens that included
“recycled” NRTIs plus unboosted PIs (SQV,
IDV) and NNRTIs (NVP, EFV)
 Never consistently achieved viral
suppression
 HIV genotype in 2007 while receiving
LPV/RTV + ABC/3TC (HIV-1 RNA: 1200
c/mL; CD4+ cell count: 300 cells/ mm3)
‒ NRTI: M184V, L74V (resistance to 3TC,
FTC, ABC)
‒ NNRTI: K103N (resistance to EFV, NVP)
‒ PI: D30N, L90M (resistance to NFV, SQV)
 Placed on new regimen of DRV/RTV
twice daily + RAL twice daily + etravirine
twice daily
 Viral suppression since then (2007)
 Asks if he can take a simpler regimen

Poll 8: How would you manage this patient’s ART
regimen?
A. Continue current therapy (4 pills twice daily)
B. Switch to once daily DRV/COBI + DTG + DOR (3 pills once daily)
C. Switch to DRV/COBI/FTC/TAF (1 pill once daily)
D. Switch to BIC/FTC/TAF (1 pill once daily)
E. Switch to long-acting CAB and RPV (2 injections once a month)
F. Something else

DHHS: Switching Regimens in Patients With Viral
Suppression and Drug Resistance
 “Patients with prior drug resistance can be switched to a new regimen based
on their ARV history and resistance testing results”
 Some data on within-class switch from 1 high resistance barrier drug to
another (DTG  BIC): Study 380-4030
 No direct data on between-class switch from 1 high resistance barrier drug
to another (boosted PI to a BIC or DTG-containing regimen + fully active
NRTI)
‒ Theoretical support from Study 380-4030
‒ Indirectly supported by superior efficacy of DTG compared with boosted
PI in patients with first-line failure and resistance: DAWNING study
DHHS ART Guidelines. December 2019. Slide credit: clinicaloptions.com

Between Class Switching With Underlying Resistance
 SWITCHMRK results warned of switching from high barrier to low
barrier resistance drug in patients with underlying resistance[1]
 Viral suppression can be maintained by boosted PIs and high resistance
barrier INSTIs (DTG and BIC) when only 1 accompanying NRTI is fully
active, unlike lower resistance barrier drugs (eg, EVG, RAL, NNRTIs)[2]
 Switching 1 low barrier drug for another is effective in those with
multidrug resistance (eg, EVG for RAL as with switch to DRV +
EVG/COBI/FTC/TAF)[3]
 What about boosted PI to high barrier INSTI switch with underlying
resistance?
1. Eron. Lancet. 2010;375:396. 2. DHHS ART Guidelines. December 2019. 3. Huhn. JAIDS. 2017;74:193. Slide credit: clinicaloptions.com

SWITCHMRK: A Cautionary Tale of Between Class
Switches
 Randomized, double-blind trials in which virologically suppressed patients continued
LPV/RTV-based regimen or switched to RAL-based regimen (N = 702)
 Underlying resistance matters: % with HIV-1 RNA < 50 c/mL for RAL vs LPV/RTV by
investigator report of previous virologic failure: no, 89% vs 90%; yes, 77% vs 92%
Switch to RAL
Continue LPV/RTV
50
60
70
80
90
100
0 4
Wks
HIV-1
RNA
<
50
c/mL
(%)
8 12 24
87%
81%
∆: -6.6 (95% CI: -14.4 to 1.2)*
SWITCHMRK-1 94%
88%
*Prespecified noninferiority margin: -12%.
Eron. Lancet. 2010;375:396.
50
60
70
80
90
100
0 4
Wks
HIV-1
RNA
<
50
c/mL
(%)
8 12 24
∆:-5.8 (95% CI: -12.2 to 0.2)*
SWITCHMRK-2

Evidence of High Resistance Barrier With DTG and BIC
 No emergent resistance with virologic failure in either treatment naive
or switch studies of DTG or BIC plus 2 NRTIs[1]
 Rare reports of emergent resistance in clinical practice or with DTG
plus 3TC[2]
 DTG superior to RAL and LPV/RTV in treatment-experienced patients
with resistance[1,3]
 BIC/FTC/TAF noninferior to DTG + FTC/TAF or FTC/TDF in suppressed
patients with NRTI resistance[4,5]
1. Cahn. Lancet. 2013;382:700. 2. Mahomed. South Afr J HIV Med. 2020;21:1062. 3. Aboud. Lancet Infect Dis. 2019;19:253. 4. Acosta. CROI
2019. Abstr 0551. 5. Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com

DAWNING: Virologic Response at Wk 48
 Patients with VF on first-line NNRTI + 2 NRTIs switched to DTG or LPV/RPV +
2 NRTIs (≥ 1 fully active NRTI per GT resistance testing at screening); no
primary resistance to INSTIs or PIs
 Emergent INSTI and INSTI + NRTI
resistance at CVW with DTG: n = 2
 Emergent NRTI resistance but no PI
resistance at CVW with LPV/RTV: n = 3
1. Aboud. Lancet HIV. 2019;6(9):e576-e587. Slide credit: clinicaloptions.com
DTG +
2 NRTIs
LPV/RTV +
2 NRTIs
*P < .0001 for superiority.
HIV-1
RNA
<
50
c/mL
(%)
[1]
ITT-E PP
219/
312
84
70
261/
312
219/
312
246/
283
204/
274
87
74
100
80
60
40
20
0
n/N =
Δ 13.8*
(7.3-20.3)
Δ 12.3
(5.8-18.7)
DTG Arm BL At VF
Patient 1 RT: K70E,
M184V
RT: M184V;
INSTI: H51H/Y, G118R; E138E/K: R263K
Patient 2 RT: M184V,
K219K/E
RT: D67N,* M184V;
INSTI: G118R
*Did not confer resistance to either NRTI taken during trial.

DAWNING: Virologic Response by Presence of M184V/I
and Use of 3TC or FTC at Wk 48
Brown. CROI 2019. Abstr 144.
DTG + 2 NRTIs
LPV/RTV + 2 NRTIs
Virologic Outcomes (ITT-E)
219/
312
85
72
187/
220
152/
210
33/
41
30/
42
80
71
HIV-1
RNA
<
50
c/mL
(%)
100
80
60
40
20
0
n/N =
Use of
3TC or FTC
No use of
3TC or FTC
12.6 Δ 9.1
41/
51
37/
60
Δ 18.7
80
62
No M184V/I
M184V/I  Other NRTI Mutations

Study 380-4030: Switch to BIC/FTC/TAF From DTG +
FTC/(TAF or TDF)
 Randomized, double-blind, active-controlled phase III noninferiority trial
Sax. Clin Infect Dis. 2020;[Epub]. Slide credit: clinicaloptions.com
Adults receiving DTG + FTC/(TAF or TDF) with
HIV-1 RNA < 50 copies/mL for ≥ 3-6 mos,* no known
INSTI resistance,† and no previous VF on INSTI
(N = 565)
BIC/FTC/TAF QD
(n = 284)
DTG + FTC/TAF QD
(n = 281)
Wk 48
*3 mos if no known NRTI resistance mutations, 6 mos with known/suspected resistance.
†Documented or suspected NRTI, NNRTI, or PI resistance permitted.
Stratified by known/suspected NRTI resistance at BL
(K65R or ≥ 3 TAMS vs other NRTI RAMs vs none)
 Primary endpoint: HIV-1 RNA ≥ 50 c/mL at Wk 48 by FDA Snapshot algorithm
‒ Noninferiority margin: 4%

Study 380-4030: Virologic Outcomes at Wk 48
 Patients with viral suppression on stable triple DTG-based ART switched to BIC/FTC/TAF or
continued DTG-based ART; documented or suspected NRTI, NNRTI, or PI resistance permitted
‒ Preexisting NRTI resistance: 25% in BIC/FTC/TAF arm and 24% in DTG-based ART arm
Sax. Clin Infect Dis. 2020;[Epub].
HIV-1 RNA
< 50 c/mL
HIV-1 RNA
≥ 50 c/mL
No Virologic
Data
1/
284
3/
281
265/
284
256/
281
22/
281
18/
284
Virologic Outcomes (FDA Snapshot)
BIC/FTC/TAF
(n = 284)
DTG + FTC/TAF
(n = 281)
Patients
(%)
n/N =
100
80
40
60
20
0
< 1 1
93 91
6 8
-4 -2 0 2 4
Favors DTG + FTC/TAF
Favors BIC/FTC/TAF
-0.7
1.0
-2.8
HIV-1 RNA ≥ 50 copies/mL
Treatment Difference, % (95% CI)

Study 380-4030: Viral Suppression After Switch From
DTG to BIC by Baseline NRTI Resistance
 HIV-1 RNA ≥ 50 c/mL not observed in any patient with preexisting NRTI
resistance
Sax. Clin Infect Dis. 2020;[Epub]. Slide credit: clinicaloptions.com
Virologic Outcomes at Wk 48 (FDA Snapshot) BIC/FTC/TAF (n = 284)
DTG + FTC/TAF (n = 281)
100
80
60
40
20
0
Overall K65R or ≥ 3 TAMs Other NRTI Resist. No NRTI Resist. No M184V/I M184VI ± Other
Resist.
91
86
94 93
87 87
91
85
91
86 87 85
Data suggest switching 1 high-resistance barrier drug for another may be effective in
patients with viral suppression, even in the setting of underlying resistance
HIV-1
RNA
<
20
c/mL
(%)
257/
284
241/
281
n/N =
15/
16
13/
14
48/
55
46/
53
194/
213
182/
214
216/
237
212/
247
41/
47
29/
34

BRAAVE 2020: Impact of BL Resistance on Outcomes
Following Switch to BIC/FTC/TAF in Black PLWH
 2:1 randomized, open-label, active-controlled
phase III study
 Evaluated switch from BL regimen (2 NRTIs +
third agent) to BIC/FTC/TAF in virologically
suppressed black PLWH (N = 495)
 Switch to BIC/FTC/TAF noninferior to
remaining on BL regimen at Wk 24
‒ Wk 24 was primary efficacy endpoint
 Patients with BL NRTI resistance remained
suppressed at Wk 24
Hagins. CROI 2020. Abstr 36. Slide credit: clinicaloptions.com
BL ARV
Resistance, %
BIC/FTC/TAF
(n = 330)
Continue BL
Regimen
(n = 165)
NRTI
 M184V/I
13
9
16
12
NNRTI 21 19
PI 11 15
Wk 24 Virologic Outcomes
HIV-1
RNA
<
50
c/mL
(%)
100
80
40
60
20
0
Yes
NRTI Resistance
98 96
BIC/FTC/TAF
BL regimen
No Yes
M184V or M184I
No
96 95 97 95 96 95
n = 44 26 269 132 31 20 282 138

99 98 99 100 100
Series 1
Switching to BIC/FTC/TAF in Patients With HIV and Pre-
Existing M184V/I
 Pooled analysis of 6 phase III studies:
N = 2034
‒ Viral suppression at baseline
‒ M184V/I detected in 10%
 HIV-1 RNA < 50 copies/mL at last visit
post-switch
‒ All patients: 99%
‒ With vs without M184V/I: 99% vs 98%
‒ No treatment-emergent resistance
Patients
(%)
HIV-1 RNA < 50 Copies/mL at Last Visit
M184V/I
*Patients with baseline data.
Andreatta. J Int AIDS Soc. 2020;23(suppl 7):105. Slide credit: clinicaloptions.com
All Patients*
(n = 1825)
100
80
40
60
20
0
All
(n = 182)
+NNRTI-R
(n = 97)
+PI-R
(n = 58)
+INSTI-R
(n = 4)

Proviral HIV DNA Genotype: Acquiring Resistance Data
 DNA (archive) genotype[1,2]
‒ Sequences mutations in cell-associated proviral DNA
‒ Can be assessed at any HIV-1 RNA level, including undetectable
‒ Less sensitive than cumulative RNA genotypes
 Concordance between DNA and RNA genotypes varies by study and ARV
class (26% to 84%)[2,3]
 Study 1824: switch to EVG/COBI/FTC/TAF among virologically suppressed
patients with M184V/I mutation on RNA assay[4]
‒ M184V/I detected with DNA assay in only 48% (40/84) of screened patients
1. Delaugerre. HIV Med. 2012;13:517. 2. Wirden. J Antimicrob Chemother. 2011;66:709.
3. Derache. PLoS One. 2015;10:e0117430. 4. Margot. IAS 2019. Abstr MOPEB249. Slide credit: clinicaloptions.com

DHHS Guidelines: Recommendations on Proviral DNA
Genotyping
 Proviral DNA genotyping can be considered for individuals with a
suppressed viral load, particularly if complex or semi-complex
preexisting resistance is suspected
 Results should be interpreted with caution; proviral genotyping may
miss some or all preexisting mutations
“… for individuals who have experienced multiple prior
failures, a prolonged history of prior ARV regimens, and/or for
whom genotypic resistance test results are not available, it
may be appropriate to utilize proviral DNA genotypic testing.”
DHHS Guidelines. December 2019.

Review of Our 3 Cases and Proposed Switch Strategies
 Switching ART in a Patient With Daily Pill Fatigue
‒ Optimal switch: Long-acting injectable CAB and RPV, monthly
‒ Need to monitor adherence, vaccinate against hepatitis B
 Switching ART to Avoid Comorbidities
‒ Optimal switch: DTG/3TC, one pill daily
‒ Not approved for eGFR < 50 mL/min, but likely safe
 Simplifying ART in the Context of Known Multidrug Resistance
‒ Optimal switch: BIC/FTC/TAF, one pill daily
‒ Limited data on use of this strategy with multiclass resistance, but encouraging
data from switches with active TAF and BIC

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