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Routine 1st-line resistance testing in the current treatment era: now is not the time
Emily P. Hyle, MD MScDivision of Infectious Diseases
Massachusetts General Hospital Harvard Medical School
XXVII International Workshop on HIV Drug Resistance and Treatment Strategies
October 23rd, 2018
Supported by NHLBI (K01HL123349), NIAID (R01AI042006),and Claflin Distinguished Scholars Award
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Financial disclosures
• I have no financial disclosures
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Key points
• HIV DR testing can improve clinical outcomes but only after programmatic strengthening
• Rollout of DTG further reduces the benefits of routine HIV DR testing in the general population
• Resources can likely best be used by improving VL monitoring
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Global objective
• To optimize the scale-up and sustainability of ART access and viral suppression worldwide to improve life expectancy and decrease transmissions
1. Improve ART effectiveness and durability
2. Utilize available resources efficiently
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ART scale-up is unprecedented …
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36.9
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People livingwith HIV
Aware of HIVstatus
On treatment Viral loadsuppressed
… Ongoing scale-up is still needed
6UNAIDS/WHO estimates reported July 2018
90%
90%90%
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Finding efficiencies in HIV care
PEPFAR 2018 Progress Report.
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4
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Roadmap
Clinical impact of HIV DR testing
Resource utilization
Opportunity costs
Programmatic challenges
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Roadmap
Clinical impact of HIV DR testing
Resource utilization
Opportunity costs
Programmatic challenges
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INSTI genotype?Re-start regimenStart/switch regimen
EFV+ 2 NRTI
DTG+ 2 NRTI
PI+ 2 NRTI
DTG+ 2 NRTI
DTG (BID)+ DRV/r (BID)
+ 1-2 NRTI
1st Line 2nd Line 3rd Line
WHO 2018. http://www.who.int/hiv/pub/guidelines/ARV2018update/en/
WHO regimen guidelines (July 2018)
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TLE initiation: no HIV DR testing
11
VL Monitoring
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART
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TLE initiation: HIV DR testing
12
VL Monitoring
HIV DR Test
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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Can NNRTI-R virus suppress with EFV?
• 837 patients initiated TDF/FTC/EFV in rural KZN and had at least 1 VL in follow-up
• Overall, 94.5% suppressed at 12 months
13Derache and Iwuji et al. CID 2018
PDR N= Time to suppression (months)
No PDR 765 (91%) 3.5
NNRTI-R 67 (9%) 4.1
NRTI/NNRTI-R 5 (<1%) 11.7
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Transmitted INSTI-R
• Very rare
• Not all INSTI-R mutations have clinical consequences– DTG will be active against many INSTI mutations
• Koulias et al. used simulation modeling to evaluate INSTI-R testing at ART initiation:– As long as 20% of transmitted INSTI-R mutations
suppressed with DTG, it was not clinically beneficial or cost-effective to test before ART start in the US
– Assumption: VL monitoring!
16Koullias et al. CID 2017
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HIV DR testing at 1st-line ART initiation
• So many tests!– Benefits a small percentage of PWH – Insufficient laboratory capacity– Will add delays to ART start for everyone
• Minimal clinical benefit for patients starting TLD– Low PDR– Some INSTI mutations will suppress on DTG
• Alternative method to assess for failure– VL monitoring
• Costly
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TLE failure: no HIV DR testing
18
VL #1
ART switch
VL #2
EAC
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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TLE failure: HIV DR testing
19
VL #1
ART switch
VL #2
EAC
HIV DR Test
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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Benefits of HIV DR testing
• If susceptible virus: – Reduces unnecessary switch to later lines of ART
• Monthly ART cost will be lower
• Better tolerated ART regimens
• Additional lines of ART reserved for future need
• If resistant virus: – Prompts appropriate regimen start/switch BUT
• Genotype results must be interpreted
• Someone must be empowered to make the switch
• Next-line ART must be available
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CountryLife
expectancy Cost Conclusion
Rosen 2011 South Africa
NA --Cost-neutral
Levison 2013 South Africa
↑ ↑ Cost-effective($900/YLS)
Phillips 2014 Zimbabwe ↑ ↑ Not cost-effective
CEA: genotype at 1st-line ART failure
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CEA: genotype at failure
• No analyses published regarding genotype after failure on INSTI regimen
• Genotype testing was cost-neutral or CE– ~80% of patients fail ART with resistant virus– Unnecessary switches are costly bc 2nd-line ART is 2-
5x more expensive than 1st-line ART– HIV DR testing prompts appropriate switches but
must not create delays (Not CE if >5 months)
• HIV DR testing not CE– Benefits of PI-based ART for poorly adherent– Not all switch to 2nd-line, even with HIV DR test
Rosen et al. JIAS 2011; Levison et al. CID 2013 Phillips et al. Lancet HIV 2014.
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TLE failure: HIV DR testing – reality?
23
VL #1
VL #2
EAC
HIV DR Test
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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HIV DR testing doesn’t solve inaction
• Why do patients fail 1st-line ART for prolonged periods of time?
– Virologic failure goes unrecognized
– Clinicians do not recommend 2nd-line despite VF
– 2nd-line is not available (stockouts)
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HIV DR testing doesn’t solve inaction
• Why do patient fail 1st-line ART for prolonged periods of time?
– Virologic failure goes unrecognized
• Improve VL monitoring
– Clinicians do not recommend 2nd-line despite VF
• Empower clinicians to advocate for 2nd-line ART after repeat VL remains detectable
– 2nd-line is not available (stockouts)
• Improve supply chains
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Roadmap
Clinical impact of HIV DR testing
Resource utilization
Opportunity costs
Programmatic challenges
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Test costs
• Usually described as “$XX/test”
• Such estimates rarely include many of the important contributors to what it takes to deploy a diagnostic test
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Resource utilization
• Laboratory infrastructure– Capital costs
– Maintenance costs
• Fixed versus marginal costs– Fixed: for test availability (machine, staff salaries,
QC)
– Marginal: per test (reagents, staff time)
• Additional costs– Transport of specimens
– Communication of results with care providers
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Resource utilization ≠ per test costs
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Cost component of POC-CD4 Mobile clinic Clinic
Cost for QC materials ($/day) $0.43 $0.43
Machine start up (hours/day) 0.5 0.5
Salary ($/hour) $14.67 $8.82
Salary cost for QC ($/day) $7.33 $4.41
Total cost for QC ($/day) $7.76 $4.84
Adapted from Larson et al. PLoS One. 2012
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Resource utilization ≠ per test costs
30
Cost component of POC-CD4 Mobile clinic Clinic
Cost for QC materials ($/day) $0.43 $0.43
Machine start up (hours/day) 0.5 0.5
Salary ($/hour) $14.67 $8.82
Salary cost for QC ($/day) $7.33 $4.41
Total cost for QC ($/day) $7.76 $4.84
Adapted from Larson et al. PLoS One. 2012
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Roadmap
Clinical impact of HIV DR testing
Resource utilization
Opportunity costs
Programmatic challenges
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Anticipated challenges with DR testing
• New algorithm needed for providers
– Who will be trained to interpret genotype results?
– Who will be empowered to switch regimens?
• Avoid re-centralization
• Do not divert resources from VL scale-up
• Ensure accessibility and affordability of 2nd-line
• Given challenges surrounding DTG, now is not the time to add program complexity
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Roadmap
Clinical impact of HIV DR testing
Resource utilization
Opportunity costs
Programmatic challenges
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Opportunity costs
• What will not be funded if routine HIV DR testing is started?
• Would scale-up of VL monitoring slow?– Only 10% of focus countries report ≥90% of PWH
on ART with annual VL
• Would ART availability be compromised?– 48% of focus countries reported ART stock outs
in past year
WHO Global Action Plan on HIV Drug Resistance 2017-2021. July 2018
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Future steps
• Ongoing improvement in programmatic flow– Consistent viral load monitoring– Increased switch to 2nd-line for patients failing 1st-line– Reduce stock outs
• Special populations– Children
• Surveillance ≠ clinical decision-making– Further drug resistance data collected now to inform future
guidelines
• Hope for the best, but anticipate the worst– Now is the time to develop a plan; simulation modeling can
provide estimates and project outcomes35
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Key points
• HIV DR testing can improve clinical outcomes but only after programmatic strengthening
• Rollout of DTG further reduces the benefits of routine HIV DR testing in the general population
• Resources can likely best be used by improving VL monitoring
36
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37
CEPAC-International Research Team
BrazilBeatriz Grinsztejn, MDPaula Luz, PhDClaudio Struchiner, PhDValdilea Veloso, MD
FranceDelphine Gabillard, PhDGuillaume Mabileau, MScYazdan Yazdanpanah, MD, PhD
Côte d’Ivoire Xavier Anglaret, MD, PhDChristine Danel, MDSerge Eholie, MD, PhDEugène Messou, MDEric Ouattara, MD, MPH
ZimbabweBarbara Engelsman, MDAngela Mushavi, MDKaren Webb, PhD
Thank You
United StatesAudrey BangsIngrid Bassett, MD, MPHBridget BundaAngrea Ciaranello, MD, MPHSydney CostantiniCaitlin Dugdale, MDJulia FooteKenneth Freedberg, MD, MSc
South AfricaLinda-Gail Bekker, MD, PhDNeil Martinson, MBBCh MPH Robin Wood, MBBCh, Mmed
IndiaNagalingsewaran Kumarasamy, MBBSNomita Chandhiok, MD
Fatma Shebl, MD, PhDPaul Sax, MDJustine Scott, MPHTijana StanicMadeline SternPamela TorolaRochelle Walensky, MD, MPHMilton Weinstein, PhD
Aditya GandhiEmily Hyle, MD, MScEmily MarteyNicole McCannLucia MillhamAmir Mohareb, MDAnne Neilan, MD, MPH
Supported by:
National Heart, Lung, and Blood Institute (K01HL123349)National Institute of Allergy and Infectious Disease (R01AI042006, R37AI093269)
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SUPPLEMENTARY SLIDES
38
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INSTI genotype?Re-start regimenStart/switch regimen
EFV+ 2 NRTI
DTG+ 2 NRTI
PI+ 2 NRTI
DTG+ 2 NRTI
DTG (BID)+ DRV/r (BID)
+ 1-2 NRTI
1st Line 2nd Line 3rd Line
WHO 2018. http://www.who.int/hiv/pub/guidelines/ARV2018update/en/
WHO regimen guidelines (July 2018)
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TLE Failure: HIV DR Testing
40
VL #1
ART switch
VL #2
EAC
HIV DR Test
NNRTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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TLD Failure: No HIV DR Testing
41
VL #1
ART switch
VL #2
EAC
INSTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
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TLD Failure: HIV DR Testing
42
VL #1
ART switch
VL #2
EAC
HIV DR Test
INSTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
LM8
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Slide 42
LM8 Option #1Lucia Millham, 2018/10/22
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TLD Failure: HIV DR Testing
43
VL #1
ART switch
VL #2
EAC
HIV DR Test
INSTI-R 1st-line ART Failing 1st-line ARTSuppressed 1st-line ART Suppressed 2nd-line ART
LM9
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Slide 43
LM9 Option #2Lucia Millham, 2018/10/22
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Clinical Decision-Making
ART Initiation ART Switch
TLE TLD TLD
TLD ? PI-based ART
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** NRTI resistance pattern used to determine NRTI pair
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Data Are on the Horizon
Study Intervention Status
DAWNING DTG vs LPV/r Awaiting final data
D2EFT DRV/r + 2NRTIDTG + TDF/XTCDRV/r + DTG
Enrolling
NADIA DTG vs DRV/r+TDF/XTC vs AZT/3TC
Protocol finalization
45Adapted from ClinicalTrials.gov
Inclusion criteria: patients failing NNRTI + 2NRTI
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VL Monitoring is Essential
• Among PWH who have close follow-up with VL testing to assess response to ART, HIV DR testing
– Reduce transmissions
– Prompt adherence counseling
– Trigger resistance testing or empiric ART switch
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Clinical benefits of HIV DR testing
• Pretest probability of resistance:
– Prevalence of pretreatment drug resistance
– Likelihood of developing acquired drug resistance
• Genetic barrier to resistance
• Tolerability of regimens (adherence)
• Frequency of stockouts
• Selection of optimal ART regimen
– Depending on HIV DR test result