HIV Clinical Management: Antiretroviral Therapy...
Transcript of HIV Clinical Management: Antiretroviral Therapy...
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HIV Clinical Management:Antiretroviral Therapy and Drug Resistance
Judith S. Currier, MD, MSc
Professor of Medicine
University of California, Los Angeles
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Disclosures:Research Grant from Theratechnologies to UCLA
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Clinical Management Topics
• Initial Antiretroviral Therapy• Efficacy and Tolerability
• Resistance • Epidemiology
• Resistance Testing
• Second and Third Line ART
• Future priorities
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ART Recommended for All People with HIV
ART recommended for early HIV infection[1,2]
– DHHS and WHO guidance recommend ART for all HIV-infected pts worldwide, regardless of CD4+ cell count
ART recommended for pregnant with early HIV infection[1]
1. DHHS Guidelines. January 2016. 2. WHO. September 2015.
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Number of people receiving antiretroviral treatment
Source: UNAIDS/WHO estimates.The red shading shows future targets.
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Antiretroviral Therapy : What to Start in 2017
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Antiretroviral Therapy : What to Start in 2017
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Efavirenz based ART as First Line
• Advantages
• Single tablet regimens available at low cost
• Over 15 million person years of treatment experience with efavirenz 600 mg/day
• Generally well tolerated
• Safely used in pregnancy and for patients with TB
• Challenges
• CNS side effects are common
• Drug interactions
• Low barrier to resistance
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Alternative First Line ART
• Lower dose EFV 400 mg
• Better tolerated• Lower cost
• Dolutegravir
• Superior virologic outcomes compared to EFV • Fewer drug Interactions• Very low risk of resistance at failure: no cases of resistance
in first line clinical trials with DTG• Limited data in children, pregnant women and TB-
coinfection• Will Immune Reconstitution Inflammatory Syndrome (IRIS)
be a problem?
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Using INSTI may enhance the risk of IRISART with INSTI N=398
ART without INSTI N=1889
Pre-ART CD4 cell count
34 84
Pre-ART Viral Load 5.3 5.2
IRIS Cases, N (%) 12 (3.0) 29 (1.5)
M. tuberculosis 5 (42%) 7 (58%)
M. avium 2 (20%) 8 (80%)
Progressive Multifocal Leukoencephalopathy
1 (16.7%) 5 (83.3%)
CMV 2 (40%) 3 (60%)
Kaposi sarcoma 2 (50%) 2 (50%)
Toxoplasmosis 0 2
2287 Patients Multi-center cohort study in France IRIS events requiring hospitalization, mainly related to mycobacterial infections, were rare but twice as frequent among patients with CD4 cells below 200/mm3 who initiated INSTI-based ART regimen compared those without an INSTI
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Neuropsychiatric AEs in Dolutegravir
• Retrospective analysis on 2260 HIV+ patients in France
• Median age 50
• CD4 591
• DTG discontinuation for Neuropyschiatric (NP)-AEs was 5.4%
• Irritability and sleep disturbances were the most frequently observed NP-AEs
• >60 years old, female sex, and BMI were significantly associated with NP-Aesoccurrences.
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Ongoing International Trials with DTG, EFV and EFV 400
• Pregnant women• Dolphin- 1, Dophin-2, VESTED (DTG/FTC/TAF vs DTG/TDF/FTC vs EFV/TDF/FTC)
• TB Coinfection• EFV 400 + rifampicin• EFV +NRTI vs DTG + 2 NRT in TB• TAF + rifampin
• Treatment Naïve• ADVANCE (South Africa) DTG/TAF/FTC vs DTG/TDF/FTC vs EFV/TDF/FTC• NAMSAL (Cameroun) DTG/3TC/TDF vs EFV400/3TC/TDF/
• Second Line• DAWNING 2NRTI +DTG s 2NRTI + PI/r• D2EFT DTG/DRV/r vs 2NRTI + DRV/r
Vitoria, Ford, Clayden, Pozniak and Hill. Curr Opin HIV AIDS 2017
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HIV DRUG RESISTANCE
Image from Scientific American, 1998
The presence of transmitted drug resistance to NNRTI or NRT increases risk of virologic failure on first line ART with NNRTI’s
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HIV Drug Resistance : Context is Important
• Transmitted resistance in treatment naïve
• Resistance after first line failure• Duration of failure and availability of VL monitoring
• Resistance after second line
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HIVDR in ARV-naïve Individuals
East Africa Southern Africa
West & Central Africa Latin America & Caribbean
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Pre-Rx Drug Resistancein Children in SSA
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RV 329: African Cohort Study (AFRICOS)
• Prospective observational HIV-focused cohort executed by US Military HIV Research Program with PEPFAR and Department of Defense researchsupport
• Enrolling adults aged 18+ at 11 HIV
clinic sites in 4 countries
• Current enrollment over 2600 HIV
infected and 500 HIV uninfected
participants with 6 monthly visits
• HIV outcomes measured: CD4, viral load,
genotype resistance testing at baseline
and virologic failure
• Serum, plasma and cells stored
Slide credit: Julie Ake
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Drug Resistance – ART Naïve ParticipantsUganda
n=92 (%)
Kenya
n=35 (%)
Tanzania
n=59 (%)
Nigeria
n=35 (%)
Total
n=221 (%)
Any SDRM 7 (8) 2 (6) 7 (12) 6 (17) 22 (10)
Major NRTI Resistance 2 (2) 0 (0) 1 (2) 4 (11) 7 (3)
L74V 2 (2) 0 (0) 1 (2) 1 (3) 4 (2)
M41L 0 (0) 0 (0) 0 (0) 3 (9) 3 (1)
M184V/I 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5)
Major NNRTI Resistance 3 (3) 2 (6) 5 (8) 1 (3) 11 (5)
K103N 3 (3) 2 (6) 4 (7) 0 (0) 9 (4)
Y181C 1 (1) 0 (0) 1 (2) 0 (0) 2 (1)
G190A 0 (0) 0 (0) 0 (0) 1 (3) 1 (0.5)
Major PI Resistance 0 (0) 0 (0) 0 (0) 0 (0) 0 (0)
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Impact of HIVDR between 2016 and 2030 in sub-Saharan Africa (Low/Mid-Income countries)
AIDS Deaths New Infections ART Costs
With HIVDR (fast track projections) 5.6 million 5.1 million $ 83 billion
Current level of PDR < 10%Amount attributable to HIVDR
710,000 (13%) 380,000 (7%) $ 5.0 billion (6%)
Current level of PDR ≥ 10%Amount (%) attributable to HIVDR
890,000 (16%) 450,000 (9%) $ 6.5 billion (8%)
J Infect Dis. 2017 Feb 17
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Resistance after First Line ART
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Countries contributing data to resistance analysis and HIV-1 subtype distribution
1926 individuals from 36 countriesAdapted from Lancet Infect Dis 2016; 16: 565–75
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TDF and NNRTI resistance after first line failure of TDF containing ART
CD4 < 100 risk strongest factor for TDF Resistance
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Hosseinipour, M et al. JAIDS 2017 1;75 Suppl 2:S149-S155
HIV Drug Resistance in Option B + Malawi
• Prospective study of 1269 post-partum women randomized to different strategies for promoting uptake and retention of Option B+
• At 6 months follow-up• 75 % retained in care
• Of those retained 88 % had HIV RNA obtained and 84% were < 1000 copies ml
• Among the 55 with HIV RNA > 1000; 19(35%) had HIV drug resistance
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Drug Resistance – ART Experienced Participants
Uganda
n=10 (%)
Kenya
n=21 (%)
Tanzania
n=17 (%)
Nigeria
n=17 (%)
Total
n=65 (%)
Major NRTI Resistance 2 (20) 11 (52) 10 (59) 9 (53) 32 (49)
M184V/I 2 (20%) 11 (52) 10 (59) 9 (53) 32 (49)
K70R 0 (0) 3 (14) 5 (29) 2 (12) 10 (15)
D67N 0 (0) 2 (10) 4 (24) 3 (18) 9 (14)
Major NNRTI
Resistance
3 (30) 15 (71) 14 (82) 13 (76) 45 (69)
K103N 1 (10) 7 (33) 7 (41) 10 (59) 25 (38)
Y181C 0 (0) 5 (24) 5 (29) 3 (18) 13 (20)
G190A 2 (20) 4 (19) 2 (12) 2 (12) 10 (15)
V106A/M 0 (0) 1 (5) 4 (24) 0 (0) 5 (8)
Major PI Resistance 0 (0) 0 (0) 0 (0) 1 (6) 1 (2)
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High Prevalence of HIV DR among previously unmonitored patients with Virologic Failure in Malawi
• Examined rates of HIV Drug Resistance among 1498 patients in 5 district hospital programs on first line ART
• Viral load obtained if on treatment for at least 6 months, 24 months or longer or with clinical failure
• If VL > 5000 copies, adherence counseling done with repeat VL 3 months• Sent samples for resistance testing if confirmed VL 88 (5.8%) had VF
• Among these patients with resistance testing (n=61) 95% had resistance to NRTI or NNRTI
• 50% had high level resistance to NRTI and 50% high level NNRTI• Longer duration of ART associated with higher rates of resistance
• Patients in care for longer time with VL should be prioritized to shift to second line ART
Rustein SE IDWeek2016;Abstract 1551.
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Resistance at first failure and response to second line ART
• Second line ART after NNRTI first line
• Three major studies all compared LPV/r + 2 NRTI with RAL + LPV/r
• SECOND LINE1 (2-3 NRTI +LPV/r vs LPV/r + RAL)
• EARNEST 2 (2-3 NRTI + LPV/r vs LPV/r + RAL vs LPV/r monotherapy
• SELECT (ACTG)3 (2 NRTI + LPV/r vs LPV/r + RAL )
• All 3 studies demonstrated non-inferiority of LPV/r + NRTI , no clear advantage of LPV/r + RAL
• Resistance testing was done in retrospect
1. Boyd M et al Lancet. 2013 Jun 15;381(9883):2091-9. 2. Paton N, et al N Engl J Med 2014; 371:234-247 3. LaRosa A, CROI 2017
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HIV Drug Resistance after First Line Failure in EARNESTMalawi, Uganda, Kenya and Zimbabwe
Kityo C, et al JAIDS June 2017 Suppl
• 787 adults failing first line NNRTI treatment- median duration 4 years
• Viral subtype distribution• A1 (40%; Uganda and Kenya)
• C (31%; Zimbabwe and Malawi)
• D (25%; Uganda and Kenya)
• DRM more common in subtype C
• Tenofovir resistance similar by subtype
• Subtype C resistance to ZDV, ABC, etravirine and ripivirine more common implications for second and third line
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Paradox: Impact of Baseline Resistance on Risk of Virologic Failure• No differences between arms, or after adjustment for baseline HIV-1 RNA,
Wk 4 adherence, previous TDF use, country[1]
• ACTG 5273 overall results consistent with EARNEST, SECOND-LINE trials[2,3]
1. La Rosa AM, et al. CROI 2016. Abstract 30.
2. Paton NI, et al. N Engl J Med. 2014;371:234-247.
3. Amin J, et al. PLoS One. 2015;10:e0118228.
Baseline NRTI Resistance HR for VF in Both Arms
(95% CI)
P Value
K65R, ≥ 3 TAMs, Q151M or 69 ins/del
Yes vs no (ref)0.49 (0.31-0.76) .001
IAS NRTI mutations
≥ 3 vs < 3 (ref)0.45 (0.30-0.70) < .001
K65R and/or M184V/I
No K65R but M184V/I vs no M184V/1 (ref)
K65R and M184V/I vs no M184V/1 (ref)
0.41 (0.25-0.67)
0.19 (0.08-0.44)
< .001
Slide credit: clinicaloptions.com
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Resistance Testing and Clinical Practice: More Questions than Answers• Identifying NNRTI resistance could inform the selection of first line
ART• How should surveillance data be used to inform local guidelines?
• Will first line DTG overcome this problem for first line?• Cost effectiveness analyses suggest DTG cost effective when NNRTI resistance > 10% (Hill
Abs 112, CROI 2017)
• Value of Resistance Testing in Third Line• A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize
Combination Therapy evaluating use of resistance testing for 3rd line – due to report end of 2017
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http://www.who.int/hiv/drugresistance/HIVDR_OverviewGAP_Doherty.pdf?ua=1
ART Resistance Guidelines GroupMeeting March 2017
PreventionSurveillanceResearchLaboratory CapacityGovernance
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Summary
• Clinical Management of ART is evolving • Optimal uniform first line global regimen remains a goal- we are not there yet
• Earlier treatment expansion needs to be coupled with focus on long term adherence
• Newer treatment regimens offer promise for less resistance and toxicity, cost effectiveness studies are key to guide policy
• Viral load monitoring scale up critical for earlier detection of VF and prevention of resistance
• Clinical use of resistance testing may be most effective for third line ART
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US MHRP
Zikomo