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12/8/18 Disclosures Investigator-initiated research funding Medical Management of Viiv Healthcare Gilead Sciences HIV/AIDS PrEP Clinical Cases Sulggi Lee, M.D., Ph.D. The funders have no role in study design, data collection,

slide-1
SLIDE 1

12/8/18

Medical Management of HIV/AIDS PrEP Clinical Cases

Sulggi Lee, M.D., Ph.D.

Assistant Professor of Medicine UCSF

Division of HIV, Infectious Diseases, and Global Medicine December 6, 2018

Disclosures

  • Investigator-initiated research funding

– Viiv Healthcare – Gilead Sciences

The funders have no role in study design, data collection, analysis, or publication of the work.

Case 1

  • Consult from an internist at a private medical

clinic

  • 24 yo gay-identified male compliant on oral

daily PrEP with “discordant HIV test results”

  • Initial clinical visit:

– HIV 1/2 Ag/Ab + – Geenius differentiation assay neg – Aptima qualitative RNA -

  • 1 week later:

– HIV 1/2 Ag/Ab+ – Geenius differentiation assay neg – Aptima qualitative RNA + – VL <20 copies/mL

Labs from PMD Office

slide-2
SLIDE 2

12/8/18

Case Timeline

S t a r t e d P r E P H i g h f r e q u e n c y s e x (

  • n

P r E P ) C l i n i c t e s t i n g # 1 (

  • n

P r E P ) S t u d y v i s i t # 1 ( S t a r t e d 4

  • d

r u g A R T )

  • 12 mo
  • 3 mo
  • 1 mo
  • 2 wk

1 wk 1 mo 2 mo Time

C l i n i c t e s t i n g # 2 (

  • n

P r E P ) L a s t H I V n e g ( P r E P )

CLINICAL VISIT : STD TESTING

  • HIV 1/2 Ag/Ab POS
  • Geenius differentiation neg
  • Aptima “qualitative” RNA POS
  • HIV RNA <20
  • Ultrasensitive Plasma HIV RNA neg
  • Cell-associated DNA neg
  • Cell-associated RNA POS

2/2 reps = 117 copies/106 PBMCs Repeat testing neg

PrEP x 1 year Exposure

  • HIV 1/2 Ag/Ab POS
  • Geenius differentiation neg
  • Aptima “qualitative” RNA neg

CLINICAL VISIT 2: STD TESTING RESEARCH STUDY BASELINE

  • HIV 1/2 Ag/Ab neg
  • Plasma HIV RNA <40
  • Detuned 0.07 (neg or acute)

RESEARCH ASSAYS

Pasternak Retrovirology 2013

HIV Measurements

  • Cell-associated DNA
  • Cell-associated RNA
  • Plasma HIV RNA

Plasma RNA

Clinical Plasma HIV RNA Assays

  • Aptima TMA – false positive = 0.5%

– (1 out of 200) were falsely positive when truly negative (compared to a cell-associated DNA). – Only a 0.5% chance that this is a false positive.

Fiscus JCM 2013; Pas JCM 2013

Can PrEP be “Overwhelmed?”

  • Unpublished data modeling from Bob Grant’s

SeroPrEP study

– Suggests that >90 sex acts per month might be a “threshold” that could surpass daily oral PrEP

  • Case report of 1 man who has sex with men

who was infected with wildtype virus while highly adherent to daily TDF/emtricitabine

Hoornenborg CROI Feb 2017, Seattle WA #953

slide-3
SLIDE 3

12/8/18

Incidence Assay Performance in Early HIV Infection

National HIV Curriculum at https://www.hiv.uw.edu/go/screening-diagnosis/diagnostic-testing/

But what does PrEP do to the timing of positivity and interpretation of these tests??

Effects of PrEP on NAT and Antibodies

  • Reduces and delays

RNA and p24

– Can be below LOD of NAT

  • Reduces and delays

IgM and IgG responses

– Can get false neg on “4th Gen” EIAs

  • Can get seroreversion
  • Bands on western

blot/anti-HIV antibody tests may be delayed and atypical

Keating CID 2016

RNA/p24 Ag IgM antibodies IgG antibodies IgM antibodies RNA/p24 Ag IgG antibodies Antiretroviral therapy

Acute HIV Infection Acute HIV Infection on PrEP

PrEP Interference with Incidence Testing

  • Suppressed viral replication

– False neg even with the most sensitive NAT assays

  • Interference with serological response in patient

– False neg antibody results, delayed responses, seroreversions with EIA and WB

(Hare CID 2006; Killian AIDS Res Hum Retr 2006; Stephenson OFID 2016)

  • Unusual patterns of serology and NAT testing

– NAT ‘positive’ signal without seroconversion – Negative, indeterminate western blots/EIAs

Antibody Response is “Aborted” with Early ART and Resumes with Treatment Interruption

Stephenson OFID 2016

N = 7 aviremic N = 10 viremic

slide-4
SLIDE 4

12/8/18

Stevenson Scientific American 2008

Virus Persists in Dormant T Cells

ART DO NOT kill these cells!

Implications for HIV Cure

PrEP Demo Participant Started ART ~12 Days after HIV Infection . . .

Henrich Deeks PLoS Med 2017

Patient started on ART ~10 days from infection 220 copies/mL

Henrich Deeks Plos Med 2017

Decided to Undergo Analytic Treatment Interruption – Rebounded at Day 230

CD4+ Count Plasma HIV RNA

Day 230

Case Summary

  • Very difficult to definitively confirm if patient was

indeed HIV+

– Patient elected to continue with full ART – No issues with stigma or carrying diagnosis of HIV – PMD in agreement given high risk sex activity

  • Alternatives

– Remain on PrEP and monitor

  • If new HIV infection – will not know if new or early

suppressed?

– Analytic treatment interruption off all therapy

  • Not feasible given high risk frequent sex
  • Unclear length of follow-up to assess viral rebound
slide-5
SLIDE 5

12/8/18

Case 2

  • 21 year-old Latino man who has sex with male,

cis female and trans female partners, on oral daily PrEP

  • Reported “excellent adherence”
  • At 13-month PrEP visit, rapid HIV Ab neg
  • But 5 days later, plasma HIV RNA =559 copies/mL

P r E P I n i t i a t i

  • n

3 6 10 12 13 13.3 14

Months

Testing

  • STAT PAK neg
  • Pooled RNA neg
  • Urine GC pos
  • 3 Partners
  • STAT PAK neg
  • Pooled RNA neg
  • 3 Partners
  • STAT PAK neg
  • Pooled RNA neg
  • Urine GC pos
  • Genital HSV-2 PCR pos
  • 4 Partners
  • STAT PAK neg
  • Pooled RNA neg
  • 4 Partners
  • Urine GC pos
  • 2 Partners
  • STAT PAK neg
  • Pooled RNA POS (529

copies/mL)

  • Urine GC POS
  • 5 Partners
  • Ag/Ab POS
  • Geenius POS
  • HIV RNA 1,544 copies/mL

4

  • D

r u g A R T

adapted from Cohen Lancet HIV 2018

P r E P I n i t i a t i

  • n

3 6 10 12 13 13.3 14

Months

Testing

  • STAT PAK neg
  • Pooled RNA neg
  • Urine GC pos
  • 3 Partners
  • STAT PAK neg
  • Pooled RNA neg
  • 3 Partners
  • STAT PAK neg
  • Pooled RNA neg
  • Urine GC pos
  • Genital HSV-2 PCR pos
  • 4 Partners

Geno/Pheno

  • RT: L74V, L100I,

M184V, K103N

  • FTC resistant but

TDF susceptible (no K65R)

  • STAT PAK neg
  • Pooled RNA neg
  • 4 Partners
  • Urine GC pos
  • 2 Partners
  • STAT PAK neg
  • Pooled RNA POS (529

copies/mL)

  • Urine GC POS
  • 5 Partners
  • Ag/Ab POS
  • Geenius POS
  • HIV RNA 1,544 copies/mL

4

  • D

r u g A R T

High adherence by hair High adherence by DBS

adapted from Cohen Lancet HIV 2018

Case Continued

  • To evaluate for possible early suppressed

infection

– Additional testing of stored plasma from the visit 12 weeks prior to the diagnosis visit

  • No evidence of plasma HIV by iSCA (lower limit of

detection = 1 copy per /ml)

– Single Genome Sequencing on early sample

  • Limited viral diversity consistent with acute infection
slide-6
SLIDE 6

12/8/18

PrEP Failure is RARE!

  • There are only a few cases reported

worldwide

– Hundreds of thousands of people have used PrEP – Tens of thousands of HIV infections have been prevented. – Almost all people who use PrEP stay free of HIV

The message to send your patients is that PrEP is highly highly effective

Worldwide Reported PrEP Failures

Cohen Lancet HIV 2018

5 cases emtricitabine/tenofivir failure All compliant with PrEP 4 multiresistant HIV 4 had M184V leading to high level resistance to FTC 2 viruses that were susceptible to TDF Aberrancies in test results Low viral loads Delayed seroconversion Indeterminate western blots

Acknowledgements

Top: Enrique Martinez-Ortiz, Viva Tai, Chris Pilcher, Mike Busch, Steven Deeks, Peter

  • Hunt. Bottom: Monika Deswal, Montha Pao, Maya Ball-Burack, Rebecca Hoh,

Heather Hartig, Marian Kerbleski, Sulggi Lee. Not pictured: Raeni Miller, Claire Rappaport, Melissa Krone, Mary Ellen Kelly, Elnaz Eilkhani Lisa Harms Jeff Martin Tim Henrich Rick Hecht Kara Marson Tony Ling

Case 2: Stephanie Cohen, Darpun Sachdev, Oliver Bacon, Mary Kearney, Susa Coffey, Bob Grant, Diane Havlir, Monica Gandhi

Case 1&2: SCOPE TEAM