Dual Antiretroviral Therapy (ART): What Do We...
Transcript of Dual Antiretroviral Therapy (ART): What Do We...
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Mountain West AIDS Education and Training Center
Dual Antiretroviral Therapy (ART):
What Do We Know?
Brian R. Wood, MD
Assistant Professor of Medicine, University of Washington
Medical Director, MW AETC ECHO
Last Updated: 9/29/16
Dual ART: Outline
• Data for initial therapy
• Data for maintenance and salvage therapy
• Ongoing clinical trials
What’s In The HHS Guidelines?
• “Other regimens to consider for initial therapy if TAF, TDF,
and ABC cannot be used…”
- DRV/r + RAL (only if HIV RNA <100K and CD4 >200) [CI]
- LPV/r + 3TC (BID) [CI]
• When might this be considered?
- Renal insufficiency plus contraindication to ABC
Source: aidsinfo.gov; HHS Adult and Adolescent Treatment Guidelines
Boosted PI + Raltegravir
Dual Regimens for Initial Therapy
Study Dual ART
Regimen
Comparator N Follow-up Efficacy Outcomes and Issues
NEAT/
ANRS 143
DRV/r +
RAL
DRV/r +
TDF/FTC
805 96 weeks Non-
inferior
More failures and
resistance if CD4 <200;
trend toward more
failures if VL >100K
RADAR DRV/r +
RAL
DRV/r +
TDF/FTC
83 48 weeks Inferior Virologic efficacy 62.5%
dual vs 83.7% triple ART
ACTG 5262 DRV/r +
RAL
None 112 96 weeks 26%
failure
High rates of RAL
resistance if VL >100K
PROGRESS LPV/r +
RAL
LPV/r +
TDF/FTC
206 96 weeks Non-
inferior
Few participants with VL
>100K
SPARTAN ATV (300
mg BID) +
RAL
ATV/r +
TDF/FTC
94 Stopped at
24 weeks
Inferior More failures with
resistance and more
jaundice
NEAT/ANRS143: Raffi F et al. Lancet. 2014;384:1942-51. RADAR: Cutrell JM et al. PLoS One. 2014 Aug 29;9(8):e106221.
ACTG 5262: Taiwo B et al. AIDS. 2011;13;25(17):2113-22. PROGRESS: Reynes J et al. AIDS Res Hum Retroviruses. 2013
Feb;29(2):256-65. SPARTAN: Kozal MJ et al. HIV Clin Trials. 2012 May-Jun;13(3):119-30.
Boosted PI + Maraviroc
Dual Regimens for Initial Therapy
Study Dual ART
Regimen
Comparator N Follow-up Efficacy Outcomes and
Issues
MODERN DRV/r +
MVC (150
mg daily)
DRV/r +
TDF/FTC
797 Stopped at
48 weeks
Inferior Efficacy 77.3% dual
vs 86.8% triple ART
MIDAS DRV/r +
MVC (150
mg daily)
None 24 96 weeks 10%
failures
Failures had baseline
HIV RNA >100K
A4001078 ATV/r +
MVC (150
mg daily)
ATZ/r +
TDF-FTC
121 48 weeks Non-inferior More low-level
viremia, more
hyperbilirubinemia,
not fully powered
MODERN: AIDS. 2016;30(8):1229-38. MIDAS: Taiwo B et al. JAIDS. 2013;64(2):167-176. A4001078: Mills A et al. JAIDS.
2013;62(2):164-70.
Boosted PI or DTG + 3TC for Initial Therapy
Study Dual ART
Regimen
Comparator N Follow-
up
Efficacy Issues
GARDEL LPV/r +
3TC (BID)
LPV/r +
2 NRTI’s
426 48 weeks Non-inferior High pill burden, LPV
no longer
recommended,
comparator NRTI’s
mostly AZT & 3TC
PADDLE DTG +
3TC
None 20 48 weeks 18/20
(90%) VL
<50 copies
Small study, tried to
exclude baseline VL
>100K; ACTG 5353
now recruiting (aim =
120 participants)
GARDEL: Cahn P et al. 14th European AIDS Conference. Brussels; Sept. 2013. Abstract LBPS7/6. PADDLE: Cahn P et al. AIDS
July 2016, Durban, late breaker abstract FRAB0104LB.
Dual ART for Initial Therapy
Interpretation
• Boosted PI + raltegravir: data very mixed; clearly not
reliable if advanced infection…use with caution
• Boosted PI + maraviroc: clearly inferior and not reliable
• Boosted PI or DTG + 3TC: seems to work?? potential cost-
saving future option??
Switch to Boosted PI + Raltegravir or Maraviroc
*Participants Very Carefully Selected
Study Dual ART
Regimen
Comparator N Follow-up Efficacy Outcomes and
Issues
SPARE DRV/r +
RAL
LPV/r +
TDF/FTC
58 48 weeks Non-
inferior
HARNESS ATV/r +
RAL
ATV/r +
2 NRTI’s
109 Stopped at
48 weeks
Inferior More virologic
rebound and low-
level viremia
MARCH MVC (150
mg BID) +
PI/r
MVC (300 mg
BID) or PI/r+
2 NRTI’s
560 48 weeks Inferior Inferior virologic
suppression with
dual ART
SPARE: Nishijima T et al. PLoS One. 2013;8(8):e73639. HARNESS: van Lunzen J et al. J Acquir Immune Defic Syndr.
2016;71(5):538-543. MARCH: Pett SL et al. Clin Infect Dis. 2016;63(1):122-32.
Switch to Boosted PI + 3TC for Maintenance
*Participants Very Carefully Selected
Study Dual ART
Regimen
Comparator N Follow-up Efficacy Outcomes and
Issues
SALT ATV/r +
3TC
ATV/r +
2 NRTI’s
286 48 weeks Non-
inferior
ATV no longer a first-
line agent
OLE LPV/r +
3TC (QD)
LPV/r +
2 NRTI’s
250 48 weeks Non-
inferior
LPV no longer a first-
line agent
Casado et al
(2014
research
letter)
DRV/r +
3TC
None 48 48 weeks 98%
efficacy
Single-arm, open-
label study; larger
trial ongoing
SALT: Perez-Molina JL et al. Lancet Infect Dis. 2015;15(7):775-84. OLE: Arribas JR et al. Lancet Infect Dis. 2015;15(7):785-92.
Casado et al. J Int AIDS Soc. 2014;17(4 Suppl 3):19801.
Switch to DRV/r + RPV for Maintenance
The PROBE Study
• Italian Cohort
- Prospective, open-label, pilot study
- 60 patients with suppressed HIV RNA on PI/r + 2 NRTI’s
- Randomized to switch to DRV/r + RPV or continue
- Median 6 years on ART, median 3 prior regimens
- Equivalent viral suppression at 48 weeks
Maggiolo F et al. J Acquir Immune Defic Syndr. 2016;72(1):46-51.
Conclusion: “This approach constitutes an alternative for patients
experiencing [NRTI]-related toxicities.”
Switch to DTG + RPV for SalvageTivEdO (Tivicay plus Edurant Observational Cohort)
• Italian Cohort
- 132 treatment-experienced patients
- 12.1% RNA >50 copies/mL at baseline
- 43.2% at least one prior virologic failure
- 12.1% 1-class resistance, 20.5% 2-class, 10.6% 3-class
- All switched to dolutegravir + rilpivirine
Sterrantino G et al. 14th EU Meeting on HIV and Hepatitis. May 2016, Rome, Italy.
By week 24, subjects with HIV RNA >50 copies declined from
12.1% to 0.8%; those in whom no virus was detected increased
from 67.4% to 84.4%
Switch to Dual ART for Salvage Therapy
Randomized Trials
Study ART
History
Dual ART
Regimen
Comparator N F/u Efficac
y
Issues
SECOND-
LINE
NNRTI
failure
LPV/r +
RAL
LPV/r +
2 or 3
NRTI’s
541 48
weeks
Non-
inferior
Open-label,
genotype optional,
included AZT,
endpoint VL <200
EARNEST NNRTI
failure
LPV/r +
RAL then
LPV/r
LPV/r +
NRTI’s
1277 96
weeks
Dual
therapy
non-
inferior
More resistance
and less VL
suppression with
LPV/r monotherapy
SELECT
(ACTG
5273)
NNRTI
failure
LPV/r +
RAL
LPV/r + 2 or
3 NRTI’s
515 48
weeks
Non-
inferior
SECOND-LINE: Boyd MA et al. Lancet. 2013 Jun 15;381(9883):2091-9. EARNEST: Paton NI et al. N Engl J Med. 2014 Jul
17;371(3):234-47. SELECT: La Rosa AM et al. Lancet HIV. 2016;3(6):e247-58.
Dual ART for Maintenance or Salvage
Interpretation
• Combo of boosted PI or DTG + 3TC or RPV seems most
promising
• May be considered for select patients in unique
circumstances
• We need larger, well-designed trials of modern drugs!
Systematic Review and Meta-Analysis of Dual ART
• 21 studies (11 first-line, 10 switch)
• 2,478 individuals dual ART vs. 2,343 control (triple ART)
• “Dual therapy, especially with regimens excluding maraviroc,
could be safe and efficacious, particularly in patients with
baseline viral loads <100,000 copies/mL. However, dual therapy
seems to have a greater risk of selecting resistance mutations.”
Source: Achhra AC et al. Lancet HIV. 2016 Aug;3(8):e351-60.
Virologic failure
(RR)
AE leading to
discontinuation (OR)
Resistance
mutations (OR)
First-line 1.17 0.97 2.04*
Switch 1.14 0.55 2.47
Overall 1.13 0.73 2.11*
*Statistically significant
DTG + 3TC as Initial Therapy or Simplification
Cost Effectiveness Model
Source: Girouard MP et al. Clin Infect Dis. 2016;62(6):784-91.
Results: With 50% updake of either induction-maintenance or two-
drugs for ART-naïve patients, cost savings totaled $550 million and
$800 million respectively, within five years; savings reached greater
than $3 billion if 25% of currently suppressed patients were
switched to DTG + 3TC maintenance.
Future Questions and Directions
• Ongoing trials:
- DTG + 3TC as initial therapy (ACTG 5353)
- DRV/r + 3TC as initial therapy
- Simplification to DRV/r + DTG (DUALIS)
- Simplification to DTG + RPV (SWORD1&2)
- Simplification to DRV/r + RPV
- Simplification to DRV/r + 3TC
- Simplification to IM cabotegravir-LA + rilpivirine LA (LATTE)
Source: clinicaltrials.gov