fundamentals of antiretroviral therapy · 2020-06-06 · healthcare. (updated 11/21/19) slide 3 of...
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From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Fundamentals of Antiretroviral Therapy
Michael S. Saag, MDProfessor of Medicine
Associate Dean for Global Health
University of Alabama at Birmingham
Birmingham, Alabama
Slide 2 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Financial Relationships With Commercial Entities
Dr Saag has received research grants and support awarded
to his institution from Gilead Sciences, Inc, and ViiV
Healthcare. (Updated 11/21/19)
Slide 3 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Learning Objectives
After attending this presentation, learners will be able to:
• Articulate the mechanisms of action of antiretroviral
therapy
• Describe viral dynamics and how viral replication drives
HIV pathogenesis
• Explain how antiretroviral drug resistance occurs and how
to prevent it
Slide 4 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
BACK TO BASICS
Slide 5 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA. M Saag, UAB
Slide 6 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Vir
al L
oad
101
102
1
03104
1
05
106
0 2 4 6 8 10 12
Weeks
T1/2 = 1.1 days
Slide 7 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ARS Question 1: How many HIV virions are produced
a day in an HIV infected person?
A. 1
B. ~ 1000
C. 570,342
D. ~ 1 million
E. > 1 billion
Slide 8 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 9 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
HIV Infected
Cells
Uninfected Resting
CD4+ Lymphocytes
Uninfected Activated
CD4+ Lymphocytes
Antiretroviral Rx
Latently Infected
CD4+ Lymphocytes
HIV virions
M Saag, UAB
Vir
al L
oad
101
102
1
03104
1
05
106
0 2 4 6 8 10 12
Weeks
T1/2 = 1.1 days
Slide 10 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
RNA+ cells in Lymph node vs RNA in Plasma
HIV RNA+ cells/106 LN cells
0.1 1 10 100 1000 10000
Plasm
a Viral Load (copies/m
l)
10
100
1000
10000
100000
1000000
10000000
<50
M Saag, UAB
Pla
sma
Vira
l Loa
d
Slide 11 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ARS Question 2: At steady state, when an actively
producing cell dies, it is replaced by how many newly
infected cells?
A. One
B. Twenty-Five
C. One Hundred
D. One Thousand
E. It depends on the viral load
Slide 12 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
M Saag, UAB
Slide 13 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
VL =
100,000
Slide 14 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
VL < 50
Slide 15 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 16 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 17 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 18 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 19 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 20 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 21 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Vir
al L
oad
101
102
1
03104
1
05
106
0 2 4 6 8 10 12
Weeks
T1/2 = 1.1 days
Slide 22 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 23 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 24 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
ARS Questions 3: When should antiretroviral
therapy be started? At a CD4 count of:
A. 200 cells/ul or less
B. 200 – 350 cells/ul
C. 350 – 500 cells/ul
D. 500 – 750 cells/ul
E. Any CD4 count
Slide 25 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Schouten J AIDS 2012
Co-morbid conditions common in HIV-infected adultsHIV-infected adults age 50-55 similar to uninfected adults > 65
Slide 26 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
T cell “activation” is lower in treated than untreated adults, but consistently higher than “normal”
Hunt et al JID 2003, PLoS ONE 2011 and unpublished
% C
D38+
HL
AD
R+
CD
8+
T C
ells
0
20
40
60
80
HIVNegative(n=82)
Non-Controller
(n=65)
HAART(n=132)
P < 0.001
P < 0.001
HIV –
(n=132)
HIV +
ART
(n=65)
HIV +
Untreated
(n=82)
Slide 27 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Early ART Also Appears to Reduce Residual T Cell Activation during ART
Jain et al, CROI 2011
Slide 28 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Inverse Probability Weighted Cox Regression Multivariate Analysis
*Stratified by Cohort and Year
Relative
Hazard
(RH)*
95%
Confidence
Interval
P-value
Deferral of HAART at 351-500 1.7 1.4, 2.1 <0.001
Female Sex 1.1 0.9, 1.5 0.290
Older Age (per 10 years) 1.6 1.5, 1.8 <0.001
Baseline CD4 count (per 100
cells/mm3)0.9 0.7, 1.0 0.083
• Results were similar when restricting the analysis to the 77% of
participants with baseline HIV RNA data
• Adjusted RH for deferral vs. immediate treatment was also 1.7
95% C.I. 1.4, 2.2; p <0.0001
• HIV RNA was not an independent predictor of mortality
Slide 29 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Slide 30 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Cost-Effectiveness of
Early vs. Deferred ART
• Markov modeling approach
• Johns Hopkins HIV clinic database
• “Starting ART earlier … rather than later … is a cost-effective strategy (by the generally accepted benchmark in the US).”
Mauskopf JA, et al. JAIDS 2005;39:562-569.
ART Initiation
Incremental
Lifetime
Costs
Incremental
Discounted
QALY* Gained
Cost Per
Life-Year
Gained
Cost Per
QALY* Gained
CD4 >350 vs 200-350 $19,074 0.75 (0.61) $25,567 $31,226
Slide 31
Slide 31 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Relative Time on Treatment…
30 35 40 45 50 55 60 65 70
AGE (years)
CD4 650/ul
CD4 500/ul
40 years on Rx
35 years on Rx
5 years
Slide 32
Slide 32 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Relative Time on Treatment…
30 35 40 45 50 55 60 65 70
AGE (years)
CD4 650/ul
CD4 500/ul
40 years on Rx
35 years on Rx
5 years
HARM?
Slide 33 of 51Slide 33 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Improved Clinical Outcomes With Rapid ART Initiation
▪Universal recommendations for treating all HIV-infected persons▪Systematic review of 22 studies of rapid ART initiation (including 4 RCTs)
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 (95% 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)
Ford N, et al. AIDS. 2018;32:17-23.
Slide 34 of 51Slide 34 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Expedited ART– Experience in Atlanta
• Grady reduced barriers, with goal to begin ART within 72hrs• Pre-intervention days to ART = 22, Post-intervention days to ART= 4.
Colasanti #1109
Slide 35 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Timeline of ARV Approvals
1987: 1st NRTI Approved
1995: 1st PI
1996: 1st NNRTI
2003: 1st Fusion Inhibitor
The Future: Capsid
inhibitors, Gag inhibitorsntRTI
1987: Zidovudine
1995: Lamivudine, Saquinavir
1996: Nevirapine, Ritonavir, Indinavir
2003: T-20, Atazanavir, Emtricitabine, Fosamprenavir
2005: Tipranavir
2006: Darunavir
2007: Maraviroc
2008: Raltegravir, Etravirine
2011: Rilpivirene
2012: Elvitegravir / Cobicistat
2013: Dolutegravir
2015: Tenofovir alafenamide (TAF)
2017: Bictegravir
2018: Doravirine
1991: Didanosine
1992: Zalcitabine
1994: Stavudine
1997: Delavirdine, Nelfinavir, Saquinavir
1998: Abacavir, Efavirenz
1999: Amprenavir
2000: Lopinavir/ritonavir
2001: Tenofovir Disoproxil Fumarate (TDF)
2007: 1st CCR5 Inhibitor
2008: 1st Integrase Inhibitor
Slide 36 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Site of Action of ARV Drugs
Slide 37 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
What is Immunologic Failure ?
- 1.0 -
- 2.0 -
- 3.0 -
0
100 -
200 -
300 -
6 weeks 3 months 2 years 3 years
Slide 38 of 39 From MS Saag, MD at New Orleans, LA, December 4-7, 2019, Ryan White HIV/AIDS Program CLINICAL CONFERENCE, IASUSA.
Conclusions
Understanding HIV viral life-cycle is critical to understanding
basis of ARV therapy
Viral replication is very dynamic (1- 10 billion new viruses
produced a day) and is the driving force of HIV pathogenesis
ARV therapy interrupts HIV replication ~ completely, halting the
most of the damage done by HIV
ARV therapy protects uninfected cells from becoming infected
and has no effect on cells already infected
All ARV drugs target specific sites within the viral life-cycle
Question-and-Answer Period
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