High Sensitivity HIV Testing and Translational Science around PrEP - PowerPoint PPT Presentation

High Sensitivity HIV Testing and Translational Science around PrEP Joanne S Stekle ler, M , MD MPH Associat iate P Professo ssor, D Depar artme ment o of Medicin ine Univ iversity o of Wash ashington Inte ter-Center f r for AIDS R Research Antire retrovi vira rals ls for Pr Prevention W Working G Group November 1 13, 2017

Outline - HIV testing technologies - Screening for acute HIV infection (AHI) - Impact of PrEP on HIV tests during seroconversion - Sampling of implementation science questions around HIV testing and PrEP - Not included: discussion of PrEP failures (3/12/18)

1989: State of the art technology slide courtesy of Bernie Branson

Technology: next generations slide courtesy of Bernie Branson

HIV tests: next generations HIV t V tes est Me Method Window 1 st gen EIA (Ab) viral lysate ~ 4-6 wks 2 nd gen EIA (Ab) purified HIV-1/2 Ag or recombinant ~ 3-4 wks 3 rd gen EIA (Ab) synthetic peptide, “antigen sandwich” ~ 2-3 wks detects IgM 4 th gen assay detects either antibody or p24 Ag ~ 2 wks (Ab plus p24 Ag) Pooled HIV RNA <1-2 wks (HIV NAAT) Adapted from Stekler CID 2007

Events in primary HIV infection Fiebig Staging Fiebig et al. AIDS, 2003 Sep 5; 17(13): 1871-9

The Importance of Screening for Acute HIV Infection

Why screen for acute HIV infection? Greater risk of transmission… Cohen, JID 2005

Why screen for acute HIV infection? Greater risk of transmission… Cohen et al. NEJM, 2011; 364:1943-1954

Recommended laboratory HIV testing algorithm for serum/plasma specimens

Why screen for acute HIV infection in PrEP? Drug resistance Number o of HIV Ser Seroconverters o on Activ ive Pr PrEP P Arms With HIV R Resis istan ance* HIV Infected After Enrollment, N Trial Resistant / Seroconverters mITT (oral drug) (randomized to active drug) iPrEx [1,2] 1224 0/36 Partners PrEP [3,4]* 3140 4/51 TDF2 [5] 601 0/10 FEM-PrEP [6,7]* 1024 4/33 VOICE [8] 1978 1/113 TOTAL 7967 9/243 (3.7%) Modified Total§ 7967 5/243 (2.0%) * For 454 sequencing, resistance levels >1% of variants § After exclusion of resistance likely to be transmitted Resistance with oral PrEP in AHI: 8/29 ( 29 (28%) %) 1. Liegler T, et al. J Inf Dis. 2014. 5. Thigpen MC, et al. N Engl J Med. 2012. 2. Grant RM, et al. N Engl J Med. 2010. 6. Van Damme L, et al. N Engl J Med. 2012. 7. Grant RM, et al. AIDS. 2015. 3. Baeten JM, et al. N Engl J Med. 2012. 8. Marrazzo JM, et al. NEJM. 2015 4. Lehman DA, et al. J Inf Dis. 2015.

HIV-Antibody Pools of 10 Negative Persons

HIV-Antibody 30-Sample Pools of 10 Negative Persons Master Pool

30-Sample Intermediate Pool Master Pool

Identification of Individual From Positive Pool 30-Sample Intermediat Individuals Master Pool e Pool

Selection of U.S. Pooled HIV NAAT Programs Location on Populat lation on # Te Tested # A Ab po pos Pooli ling # N NAAT po pos Yield ld North Carolina State funded 109,250 583 90:1 23 (0.02%) 3.9% Pilcher JAMA 2002 sites Pilcher NEJM 2005 Seattle MSM at PH- 27,661 551 30:1, 3 3 71 (0.25%) EIA: 12.9% Stekler AIDS 2005 funded sites POC: 29.3% Stekler STI 2013 San Francisco/LA SFCC, LA ST 4787 119 SF 50:1 12 (0.25%) 10.1% Patel JAIDS 2006 clinics LA 90:1 Atlanta HIV testing sites 2202 66 48:1 4 (0.18%) 6.0% Priddy JAIDS 2007 LA/NYC/FL STD and PH LA: 37,012 (1 st ) 427 35 (0.09%) 8.2% Patel Arch Int Med clinics NYC: 6547 (2 nd ) 29 7 (0.1%) 24.1% 2010 FL: 54,948 (3 rd ) 663 7 (0.01%) 1.1% Baltimore PH-funded sites 69,695 1766 65-70:1 7 (0.01%) 0.4% Temkin STD 2011 Newark Hospital-based 6845 115 3 3 8 (0.12%) 7.0% Martin J Clin Virol ER/outpatient 2013 Dallas Various 148,888 n/a 10:1 or 161 (0.11%) n/a Emerson J Clin Virol 20:1 2013 NYC STD clinics 65,220 n/a 16:1 40 (0.06%) n/a Borges PH Rep 2015

Selection of U.S. Pooled HIV NAAT Programs Location on Populat lation on # Te Tested # A Ab po pos Pooli ling # N NAAT po pos Yield ld North Carolina State funded 109,250 583 90:1 23 (0.02%) 3.9% Pilcher JAMA 2002 sites Pilcher NEJM 2005 Seattle MSM at PH- 27,661 551 30:1, 3 3 71 (0.25%) EIA: 12.9% Stekler AIDS 2005 funded sites POC: 29.3% Stekler STI 2013 San Francisco/LA SFCC, LA ST 4787 119 SF 50:1 12 (0.25%) 10.1% Patel JAIDS 2006 clinics LA 90:1 Atlanta HIV testing sites 2202 66 48:1 4 (0.18%) 6.0% Priddy JAIDS 2007 LA/NYC/FL STD and PH LA: 37,012 (1 st ) 427 35 (0.09%) 8.2% Patel Arch Int Med clinics NYC: 6547 (2 nd ) 29 7 (0.1%) 24.1% 2010 FL: 54,948 (3 rd ) 663 7 (0.01%) 1.1% Baltimore PH-funded sites 69,695 1766 65-70:1 7 (0.01%) 0.4% Temkin STD 2011 Newark Hospital-based 6845 115 3 3 8 (0.12%) 7.0% Martin J Clin Virol ER/outpatient 2013 Dallas Various 148,888 n/a 10:1 or 161 (0.11%) n/a Emerson J Clin Virol 20:1 2013 NYC STD clinics 65,220 n/a 16:1 40 (0.06%) n/a Borges PH Rep 2015

First 4 th generation assay was approved in U.S. in 2010 Advantages Disadvantages Missed cases Cost Initial window of 3-5d Time 2 nd window period Tech requirements

How do 4 th generation laboratory assays compare to pooled HIV NAAT? Retrospe spectiv ive studie dies Median an (rang ange) N % d detected HI HIV R RNA A not detected Stekler PHSKC 16 94% 16,300 CID 2009 Pandori SF DPH 35 80% 6373 (1177 - 14,062) J Clin Microbiol 2009 Patel STD clinics 27 85% 6961 (1827 - 21,548) FL, LA, NY Arch Int Med 2010 All studies used the Abbott ARCHITECT HIV Ag/Ab Combo Assay

Prosp spectiv ive s studie dies #4 th gen-pos Location N #NAAT-pos Yield 74,334 10.9% = 8102? ~0.04%? DeSouza AIDS Thailand 30 2015 81 “AHI” 37% NC, NYC, SF 86,836 1158 POC+ 164 POC- 0.2% Peters JAMA 2016 134 POC- (4 FN) 22.4% Peters: Median HIV RNA not detected 6019 (IQR 1225-25,866) copies/mL

How to increase recognition of AHI symptoms Approximately 50-90% of individuals have ≥1 symptoms ~2 weeks after infection Fever Fatigue Sore throat Muscle/joint aches Night sweats Headaches Diarrhea Rash Gilbert, AIDS 2013 Stekler, STI 2013 ru2hot.org http://checkhimout.ca/hottest

HIV testing and AHI symptom screening in PrEP US Public Health Service PrEP Clinical Practice Guideline, 2014

Clinical Screening for Acute Viral Syndromes and Acute HIV infection in iPrEx OLE No No HIV IV Acute HIV IV Eligible for PrEP N=1603 No Sx No Sx 1573 0 1573 Sx Sx 28 2 30 Deferred PrEP due to 1601 2 1603 Acute Viral Syndrome Sensitivity = 100% N=30 (1.9%) Specificity = 98% PPV = 6.7% NPV = 100% Acute HIV infections HIV RNA negative N=2 (6.7%) N=28 (93.3%) Delayed Start on PrEP Never started PrEP N=25 (83.3%) N=3 (6.7%) Grant et al, Lancet ID, 2014; Grant IAS 2016 (Durban)

Clinical Screening for Acute Viral Syndromes and Acute HIV infection in iPrEx OLE Symp mptom m screen ens i in iPr iPrEx OLE. E. Good sensitivity, Low PPV given the low prevalence of acute HIV infection, Require clinical training and judgment, Delayed PrEP initiation for 2% of the cohort. FTC/TDF TDF PrEP EP prevented a at least 8 infections f for every y FTC r resistan ant infec ection t that occurred ed overall. Screening for acute infection would increase benefits relative to drug resistance risks, by more than 2 fold. Yet such screens are not feasible in all settings, and are not required to achieve a favorable risk/benefit for PrEP. Grant et al, Lancet ID, 2014; Grant IAS 2016 (Durban)

Rapid HIV tests and point-of-care (POC) testing

Point-of-care HIV antibody tests ADVANTAGES DISADVANTAGES • Patient Preference? • Potential for Preliminary False-Positive Results • Potential Avoidance of Blood • Longer window period Draw/ Biohazard • More Persons Receive Results

Determine Combo (- 15) Architect Combo (-20) Bio-Rad Combo (-19) COMPLETE HIV-1/2 (-5) HIV-1/2 STAT-PAK (-5) GS 1/2+O (-12) Vironostka (+) 2 Multi-Spot (-7) Reveal G3 (-6) APTIMA (-26) OraQuick (-1) WB positive Unigold (-2) INSTI (-9) 15 5 0 25 20 10 Days before WB positive Modified from Masciotra et al, J Clin Virol 2011 slide courtesy of and Owen et al, J Clin Micro 2008 Bernie Branson

Rapid test comparison study (2/2010 - 8/2014) STD Clin inic & & Gay y Cit ity PIC Total n=3404 n=34 n=3438 Concordant Positive POC Tests 18 100 82 (77%) Discordant POC Antibody Tests 13 23 10 (9%) All POC Negative/EIA Positive 0 6 6 (6%) Acute (EIA Neg / NAAT Pos) 2 11 9 (8%) Total HIV Positive 107 (3.1%) 33 140 Stekler J Clin Virol 2016; Stekler J Clin Virol 2013; O’Neal JAIDS 2012

Screening for acute HIV infection Alere Determine HIV-1/2 Ag/Ab Combo v NAAT # AHI # AH # t teste ted detected Taegtmeyer UK 953 none PLoSOne 2011 Rosenberg Malawi 838 0/8 JID 2012 Rwanda, Kilembe 1/52 Zambia PLoSOne 2012 Conway Australia 3190 0/9 PLoSOne 2014 Duong Swaziland 18,172 0/13 J Clin Microbiol 2014 Stekler US 3438 1/11 J Clin Virol 2016 >26,591 2/93

Impact of PrEP on HIV tests during seroconversion