Disclosures Research grant support from National Institutes for - - PowerPoint PPT Presentation
12/13/19 Disclosures Research grant support from National Institutes for Health (NIH), Centers for Antiretroviral Therapy Initiation: Disease Control (CDC) & Presidents Emergency Plan for AIDS Relief (PEPFAR) From Guidelines to
Vivek Jain, M.D., M.A.S.
Associate Professor of Medicine Division of HIV, Infectious Diseases & Global Medicine San Francisco General Hospital, University of California, San Francisco
– Pros and cons, considerations, choices – Many updates from last year (4 new drugs FDA approved in 2018)
– HIV drug resistance – ART switching in virally suppressed patients – ART for pediatric or pregnant patients – Drugs still in development (but not yet FDA approved) – There's lots at this conference on all of the above, but we will focus on ART initiation
Most recent version: July, 2019 Recommended regimens are those with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use. These regimens are effective and tolerable, but have some disadvantages when compared with the regimens listed above, or have less supporting data from randomized clinical trials. However, in certain clinical situations, one of these regimens may be preferred.
Adapted Footnotes: a 3TC may be substituted for FTC, or vice versa. ABC/3TC, TDF/3TC, TDF/FTC, TAF/FTC are available as tablets, and as part of single tablet regimens. Cost, access, and availability of of STRs can influence choice of 3TC vs FTC. b TAF and TDF are two forms of tenofovir approved by the FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs. c RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily.
US DHHS ART Guidelines – October 28, 2018 Update http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf
Initial Regimens Initial Regimens “for Most People” “in Certain ClinicalSituations” BIC/TAF/FTC EVG/cobi + (TDF/FTC orTAF/FTC)
* If reproductive potential, consult guidance * If reproductive potential, consult guidance
DTG/ABC/3TC RAL/ABC/3TC
Only if HLB57-01 negative Only if HLAB57 negative and VL<100,000 * If reproductive potential, consult guidance * If reproductive potential, consult guidance
DTG + (TDF/FTC orTAF/FTC) (DRV/RTV or DRV/cobi) + (TDF/FTC orTAF/FTC)
* If reproductive potential, consult guidance
RAL + (TDF/FTC orTAF/FTC) (DRV/RTV or DRV/cobi) + ABC/3TC
* If reproductive potential, consult guidance Only if HLB57-01 negative
(ATV/RTV or ATV/cobi) + (TDF/FTC orTAF/FTC) (ATV/RTV or ATV/cobi) +ABC/3TC
Only if HLAB57 negative and VL<100,000
DOR/TDF/FTC or (DOR +TAF/FTC) EFV + (TDF/FTC orTAF/FTC)
Adapted from: US DHHS ART Guidelines – July, 2019 Update
RPV + (TDF/FTC orTAF/FTC)
Only if VL<100,000 & CD4+>200
Integrase Inhibitors
BIC DTG EVG RAL
NRTI (nucleoside analogs) Protease Inhibitors
TAF
DRV
TDF
ATV
ABC
RTV
FTC
Cobi
3TC
LPV
D4T
FPV
DDI
APV
DDC
TPV
ZDV
NFV
NNRTI (non-nucleosides)
SQV IDV
RPV ETR
CCR5 Inhibitors
DOR
MVC
EFV NVP
Fusion Inhibitors
DLV
T-20
Monoclonal Antibody
IBA
TAF TDF ABC FTC 3TC
NNRTI (non-nucleosides)
RPV
Integrase Inhibitors
BIC DTG EVG RAL
NRTI (nucleoside analogs) Protease Inhibitors
DRV RTV Cobi
NNRTI EFV RPV PI r/ATV r/DRV INSTI RAL EVG DTG
2x NRTI TDF/FTC
ABC/3TC 2x NRTI TAF/FTC
TDF/FTC
ABC/3TC
INSTI BIC DTG RAL PI r/DRV
RenalConcerns BoneConcerns Decrease in eGFR over time? Risk
tubular toxicity/ Fanconi’s syndrome? Decrease in bone density? Concomitant increase risk of fracture?
Renal Profile Bone Profile Lipid Profile better? better? worse?
Slow, small magnitude decrement in eGFR
Small risk of proximal tubular toxicity/ Fanconi’s syndrome?
Initial case reports 2002-2004
Issues: controversial topic
TDF Other
Generalized decrease in renal function TDF > Other agents; difference small Modest loss in Y1, less after that
Laprise CID 2013
A known low-level risk; forms the basisof monitoring
Japanese cohort with larger decline in eGFR with TDF vs.ABC
Nishijima AIDS 2014
Large meta- analysis including RCTs: smalldifference, perhaps 3-4 mL/min eGFR
Cooper CID 2010
in bone density after ARTinitiation
stabilization
ACTG 5202 Study: McComsey, JID,2011
Spine BMD Hip BMD
Week 48 data: Sax PE et al., Study 104/111: Lancet, 2015 Week 96 data: Wohl D et al., Study 104/111: JAIDS, 2016 Week 144 data: Arribas J et al., Study 104/111: JAIDS, 2017
Oral TAFprodrug circulates in plasma TAF taken into cells, processed to create tenofovir-diphosphate (TFV-DP, the active drug)
Virologic non-inferiority of TAF to TDF when paired with cobi/EVG
Genvoya (TAF/FTC/cobi/EVG) noninferior to Stribild (TDF/FTC/c/EVG) (Study 104/111):
Similar AE profile, lipid effects
Eron JJ et al., AMBER Study: AIDS, 2018 Orkin, C. et al., AMBER Study: HIV Drug Therapy Glasgow, Oct. 2018
Similar non-inferiority of TAF when paired with cobi/DRV
TDF/FTC+cobi/DRV: (AMBER Study)
Smaller changes in proteinuria by 4 measurements:
Less decline in eGFR:
Fewer discontinuations due to renal dysfunction:
Evidence for improved renal profile?
(Study 104/111 Data through 144 weeks)
Sax PE et al., Lancet, 2015, Wohl D et al., JAIDS, 2016, Arribas J et al., JAIDS, 2017 Arribas J et al., JAIDS, 2017
Similar data from AMBER Study:
DRV/cobi+TDF/FTC
Also note: Can use TAF for patients with eGFR≥30 whereas TDF for patients with eGFR≥60
Eron JJ et al., AMBER Study: AIDS, 2018
Evidence for improved bone profile? à (Study 104/111 Data through 144 weeks)
Less decline in bone density through 96 weeks: Smaller decrease in hip bone density:
(p<0.001) Smaller decrease in spine bone density:
(p<0.001)
Arribas J et al., JAIDS, 2017 Less drop in BMD Less drop in BMD Smaller rise in PTH Eron JJ et al., AMBER Study: AIDS, 2018
Similar data from AMBER Study:
Hip Spine Fem neck D/C/F/TAF +0.21%
D/C TDF/FTC
Compelling for some patients; less important to other patients
Lipid change from baseline to 144 weeks is worse in TAF vs.TDF:
TAF TDF Total chol. é31 é13 HDL é6 é2 LDL é19 é6 TG é20 é12
Rifamycins TAF with cobicistat
Induce CYP3A4, P-gp, and BRCP Inhibit OATP1B1, OATP1B3 Net effect of this unknown Do not co-administer rifamycins withTAF Thus, TAF dose with cobi is 10mg not 25mg
Note: TDF associated with favorable lipid profile; TAF is a move away from this favorable profile
TAF a substrate of CYP3A4, P-gp, OATP1B1, and OATP1B3
Arribas J et al., JAIDS, 2017
Cobi inhibits these à boosts TAFlevels
Renal Concerns BoneConcerns Decrease in eGFR over time? Risk
tubular toxicity/ Fanconi’s syndrome? Decrease in bone density? Concomitant increase risk of fracture?
Renal Profile Bone Profile Lipid Profile better? better? worse? Consider eGFR, proteinuria,
rifamycins in this decision… And in coming years, with generic TDF available, consider cost-benefit calculations depending on patients' insurance/coverage
ABC Hypersensitivity CardiovascularConcerns Basic biology HLA- B57-01 Testing Theoretical basisfor concern
Polymorphism of HLAB57-01 allele 4-8% of overall population positive; 2-4% among African Americans ABC binds to HLA molecule, triggering HS reaction Fully discriminative If positiveàABC contraindicated If negativeàABC safe Enhanced platelet reactivity? Platelet aggregation? Promotes ischemic CV disease? Controversial
Issues: controversial topic
Guideline Language: “Increase in CV events is associated with ABCuse in some, but not all, cohortstudies”
efficacious
resistance
booster
Triumeq, or separately
EFV, or with rifampin SINGLE Study: DTG+ABC/3TC vs. EFV/TDF/FTC
SPRING-2 Study: DTG + (ABC/3TC or TDF/FTC) vs. RAL + (ABC/3TC orTDF/FTC)
FLAMINGO Study: DTG+ (ABC/3TC or TDF/FTC) vs. DRV/RTV + (ABC/3TC or TDF/FTC)
Tivicay (DTG 50mg)
creatinine secretion, éCr will rise 0.1-0.3
polyvalent cations given (Ca+2, Mg+2, Fe+3, e.g.) à space DTG2h before or 6h after these
levels
initially thought to be <2-3% in first year
recognized
stopped DTG:
6% (sleep), 4% (GI), 4% (malaise), 3% (psychological) 2% joint/tendon/muscle, 2% neurologic
uncommon (<1%)
Curtis et al., HIV Clin Trials. 2014 de Boer et al. AIDS 2016
efficacious
resistance
single tablet Biktarvy (TAF/FTC/BIC)
Trial 1489: Biktarvy vs.Triumeq
VL>400K
Trial 1490: Biktarvy vs. TAF/FTC + DTG
Biktarvy (BIC 25mg/TAF 10mg/FTC 200mg)
Sax PE et al.,Lancet,2017 Wohl et al., LancetHIV,2019 Gallant, J et al.,Lancet,2017 Stellbrink et al., Lancet HIV,2019
creatinine: raises Cr by 0.1mg/dL
UGT1A1
gp and BCRP… so inducers can reduce TAF, inhibitors can increase TAF…
(reduces BIC and TAF)
when discontinuing: risk ofHBV flare
2h before
and food
studies
Stribild (TDF 300/FTC 200/cobi 150/EVG 150) Genvoya (TAF 10/FTC 200/cobi 150/EVG 150)
Isentress (RAL 400 BID)
potency/efficacy
(noninferior to 400mg BID; 89% vs 88% VS atW48)
Isentress HD (RAL 600 x 2 QD)
mild)
Ripamonti et al. AIDS 2014 ONCEMRK Study: Cahn P et al. Lancet HIV, 2017
rifamycins, steroids (dex)
Dolutegravir Bictegravir Raltegravir Elvitegravir
Al/Mg/Ca antacids 2h before or 6h after antacid with cations 2h before antacids with Al/Mg/Ca, Don’t combine withAl/Mg antacids… For Ca antacids, only use 400 BID RAL dose Separate from antacids by >2h H2- receptor blockers No dose adjustments needed PPI’s No dose adjustments needed
Must screen your patient for these, and good to document (esp. if on EVG) in your notes for others: ”patient on INSTI: consult pharmacy team before starting antacids, anticoagulants, antiepileptics, antidepressives, metformin, rifamycins, cations, or steroids.”
neural tube defects
tube defects (NTDs) in infants born to people who were receiving DTG at the time
– “negative pregnancy test result should be documented prior to initiating DTG in antiretroviral therapy (ART)-naive individuals of childbearing potential – DTG is not recommended for those who are pregnant and within 12 weeks post-conception – DTG is also not recommended for those of childbearing potential who are planning to become pregnant or who are sexually active and not using effective contraception – For those who are using effective contraception, use of a DTG-based regimen can be considered after discussing the risks and benefits of this drug with the patient”
effect).
– Background rate: 98 NTD s among 119,033 infants analyzed (0.08%) – On DTG: 5 NTDs amoing 1683 infants (0.30%): elevated rate, but less than seen earlier – Botswana: lacks folate fortification. ?Possible DTG antagonism of folate?
Dolutegravir Bictegravir Raltegravir Elvitegravir
QD (ART-naïve or INSTI- naïve) 1200mgQD Frequency BID: with CYP3A4 orUGT1A1
inducers, or with INSTI
QD
400mg BID QD
mutations
Genetic barrier to resistance High High Lower Lower Single tablet
Yes, Triumeq Yes, Biktarvy No Yes, Genvoya or Stribild Key side effects Nausea, diarrhea/GI disturbance, headache, insomnia Increased CK, myositis, hypersensitivity, hepatotoxicity Myositis, increasedCK (4%) myositis, hypersensitivity, hepatotoxicity, SJS/TEN hyperlipidemia
– concomitantly administer either RTV 100mg QD or cobicistat 150mgQD
– concomitantly administer RTV 100mg BID (don’t use cobicistat for boosting)
dyslipidemia, rare hepatotoxicity
Norvir: RTV 100 Prezista: DRV800 RTV100 Prezista: DRV600 Prezcobix: DRV 800/cobi150 Symtuza: DRV 800/cobi 150/ TAF/FTC
AMBER W44: Eron JJ et al., AIDS, July 2018 AMBER W96: Orkin, C. et al,, HIV Glasgow 2018, Glasgow, October 28-31,; abstract O212, Oct. 2018
EMERALD W44: Orkin, C et al., Lancet HIV, 2018 EMERALD W96: Eron JJ et al., Antivir Res, Oct 2019
– H2 blockers: give ATV 400QD 2h before or 10h after H2; give ATV300/RTV100 anytime – PPI: use omeprazole 20 or equivalent (maximum) 12h before ATV
Recommend against combining ATV with PPI RTV 100 ATV300
Edurant: RPV 25 Odefsey: RPV25/ TAF 25/FTC 200
VL>100K orCD4<200
before or 4h after RPV
Pifeltro: DOR100 Delstrigo: DOR10 TDF 300/FTC 300
0/
renal failure or liver disease
nausea, diarrhea
rifampin (rifabutin ok if use DOR 100 BID)
Sustiva: EFV 600
established
dreams
Intelence: ETR 200x2
(data support 400mgQD)
– GEMINI-1, GEMINI-2 trials: ART-naïve, VL<500K, 48W data led to FDA approval for ART naïve patients – Week 48: 91% (2 drug) vs. 93% (3 drug), pooled trials analysis – Week 96: 86% (2 drug) vs. 90% (3 drug), pooled – Risks of adherence, sub-20% M184V, the "non-perfect patient"
Cahn, P et al., Lancet, 2018 Cahn P et al., IAS2019
– SWORD-1/SWORD-2 Trials: led to FDA approved for switch of virally suppressed patients, not FDA approved for ART-naïve patients – Not mentioned in guidelines for ART initiation since not FDA approved for this
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Epzicom Truvada Evotaz Cobicistat Prezcobix TAF Descovy
April, 2016 2004 2004 January, 2015 January, 2015
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Atripla Cobicistat TAF
2006
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Complera Cobicistat TAF
August, 2011
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Odefsey Cobicistat TAF
March, 2016
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Cobicistat Stribild TAF
August, 2012
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Cobicistat Triumeq TAF
August, 2014
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Cobicistat Genvoya TAF
November, 2015
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Cobicistat Biktarvy TAF
February, 2018
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Cobicistat Symtuza TAF
July, 2018
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Delstrigo Cobicistat TAF
August, 2018
Dolutegravir Bictegravir Doravirine
Emtricitabine Lamivudine Abacavir Tenofovir Efavirenz Rilpivirine Ritonavir Atazanavir Darunavir Raltegravir Elvitegravir
Dovato Cobicistat TAF
XXXX
Dolutegravir Bictegravir Doravirine
get new pic
Initial Regimens Initial Regimens “for Most People” “in Certain ClinicalSituations” BIC/TAF/FTC EVG/cobi + (TDF/FTC orTAF/FTC)
* If reproductive potential, consult guidance * If reproductive potential, consult guidance
DTG/ABC/3TC RAL/ABC/3TC
Only if HLB57-01 negative Only if HLAB57 negative and VL<100,000 * If reproductive potential, consult guidance * If reproductive potential, consult guidance
DTG + (TDF/FTC orTAF/FTC) (DRV/RTV or DRV/cobi) + (TDF/FTC orTAF/FTC)
* If reproductive potential, consult guidance
RAL + (TDF/FTC orTAF/FTC) (DRV/cobi or DRV/RTV) + ABC/3TC
* If reproductive potential, consult guidance Only if HLB57-01 negative
(ATV/cobi or ATV/RTV) + (TDF/FTC orTAF/FTC) (ATV/cobi or ATVRTV) +ABC/3TC
Only if HLAB57 negative and VL<100,000
DOR/TDF/FTC or (DOR +TAF/FTC) EFV + (TDF/FTC orTAF/FTC)
Adapted from: US DHHS ART Guidelines – July, 2019 Update
RPV + (TDF/FTC orTAF/FTC)
Only if VL<100,000 & CD4+>200
Creatinine clearance = 55 mL/min. LDL = 68. HLAB57-01 is negative. No
– B57 negative, thus eligible. No major CV concerns. Triumeq for eGFR>50.
especially in combination with RTV/PI, which boosts TDF. Also, second line.
unboosted INSTI instead of using cobi. Also, second line.
DTG or BIC.
Creatinine = 1.6, creatinine clearance = 31 mL/min. LDL = 68. HLAB57-01 is negative. No other medical problems. Which regimen would you offer?
Creatinine = 1.6, and creatinine clearance = 31 mL/min. LDL = 68. HLAB57-01 is negative. No other medical problems. Which regimen would you offer?
– B57 negative: eligible. Some CV concerns with renal disease. – But Triumeq is only for eGFR>50.
barrier to resistance, and 3 pills where single tablet is possible
– eGFR>60 is ok, but with 1+ proteinuria, favor TAF
– OK choice, eGFR>30, but already has proteinuria…
– OK choice, eGFR>30, but already has proteinuria…
– OK choice, eGFR>50; but with CV risk factors (lipids/smoking/DM), balance CV risk with ABC vs. using TAF in patient with proteinuria
– With cardiac and renal risk factors, avoid PI if
– With proteinuria, avoid TDF. Second line.
diagnosed, VL 105,000, CD4+ =
hyperlipidemia (LDL = 140,Total cholesterol = 221), smokes 10 cigarettes/day, HBA1c = 7.1%, BUN/creatinine 14/1.2,CrCl=73 mL/min, UA: 1+
is optimal?
VL>100K (always check), would need to add entecavir with 3TC, and would prefer integrase over PI
maximum 850mg TID dose + glipizide 5mg BID, CrCl=90, UA with no
A) TDF/FTC (Truvada) +DTG
already on max dose (but might be ok)
DM2 control may get worse
B) TAF/FTC (Descovy) +DTG
C) TAF/FTC/BIC(Biktarvy)
E) TDF/FTC/cobi/EVG(Stribild)
F) TAF/FTC (Truvada) +RAL
D)ABC/3TC/DTG (Triumeq)
“DDI” = drug- druginteraction*
– Consider TDF vs.TAF
– Consider ABC vs.TDF/TAF
– Consult with experts when all NRTI’s seem problematic
– Consider prior history, drug intolerance, side effect, desire for single- tablet regimen, drug interactions – Consider DTG, BIC for most patients if possible
– Consider dosing (QD vs. BID), desire for single tablet regimen, psychiatric history, lipid profile, GI issues, renal status, likelihood of strong adherence/genetic barrier – Assess baseline VL and CD4 count
Adolescents Living with HIV. Department of Health and Human Services. Version: October 17, 2017. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 11/1/17.
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Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144
Oct;15(5):199-208. doi: 10.1310/hct1505-199. PMID: 25350958
tenofovir alafenamide, for initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017. Nov 4;390(10107):2073-2082. doi: 10.1016/S0140-6736(17)32340-1. PMID: 28867499
treatment of HIV-1 infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial.
HIV-1 patients. AIDS. 2018 Jul 17;32(11):1431-1442. doi: 10.1097/QAD.0000000000001817. PMID: 29683855
fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2017 Oct 5. pii: S2352- 3018(17)30179-0. doi: 10.1016/S2352-3018(17)30179-0. PMID: 28993180
with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018 Mar 3;391(10123):839-849. doi: 10.1016/S0140-6736(17)33095-7. PMID: 29310899
antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet. 2018 Nov 9. pii: S0140-6736(18)32462-0. doi: 10.1016/S0140-6736(18)32462-0. PMID: 30420123.
– vivek.jain@ucsf.edu – please email me anytime