Presented by HIV, ID and Global Medicine Division Zuckerberg San Francisco General Hospital and Trauma Center Department of Medicine, University of California San Francisco, School of Medicine
The Medical Management of HIV/AIDS and Hepatitis
PARK CENTRAL HOTEL SAN FRANCISCO
COURSE CHAIRS Diane V. Havlir, MD Professor of Medicine Chief, HIV, ID and Global Medicine Division University of California, San Francisco Zuckerberg San Francisco General Hospital 2018 and Trauma Center Meg D. Newman, MD, FACP UCSF Senate Emeritus – Medicine HIV, ID and Global Medicine Division Zuckerberg San Francisco General Hospital and Trauma Center
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I have no relevant financial relationships with any companies related to the content of this course. What’s New in Acute HIV Infection? Susan Little, M.D. Professor of Medicine University of California San Diego What’s New in Acute HIV Infection? What’s New in Acute HIV Infection? Rapid ART – how early is early enough? Rapid ART – how early is early enough? Post-treatment control – is it real? Post-treatment control – is it real? Using molecular epidemiology to interrupt Using molecular epidemiology to interrupt transmissions during recent infection transmissions during recent infection 3 4 How early is early enough?? Rate of Recovery of CD4+ Counts ART Start Is there a critical time period following acute HIV infection during which ART is capable of restoring ‘normal’ immune function? - “Normal” CD4 defined as 900 cells/mm3 5 Le T, et al. NEJM 2013 6 Le T, et al. NEJM 2013 CD4+ Recovery to 900 cells/mm3 Rate of Recovery of CD4+ Counts ART Start CD4>500, ART>4 mo from EDI CD4>500, ART<4 mo from EDI 3 CD4>500, ART>12 mo from EDI CD4<500, ART<4 mo from EDI 900 cells/mm CD4<500, ART>4 mo from EDI (% of participants) CD4<500, ART>12 mo from EDI CD4+ Months since Initiation of ART 7 Le T, et al. NEJM 2013 8 What’s New in Acute HIV Infection? Conclusions Modified RAPID protocol: San Diego (2014-2016) The probability of attaining a CD4 >900 on ART was greatest Clinic-based cohort of consecutive patients with newly diagnosed HIV for those who started ART within 4 months of EDI. - Including AHI, Early HIV, and chronic HIV (any CD4) Intervention: Modified RAPID Program: Each month delay in ART reduced probability of achieving a 1) Access to HIV provider within 24-48 hrs of HIV diagnosis CD4 > 900 by approximately 10%. 2) Same-day medical visit (2-4 hours) with safety and clinical care labs Chance of achieving CD4>900 reduced by 94% if CD4<500 at 3) ART Provided: elvitegravir, cobicistat, emtricitabine & tenofovir alafenamide ART start, independent of EDI. 4) Telephone f/u within 14 days to review labs, review adherence, etc. 5) Case Management: insurance assessment and linkage to care <25 % of ART-naïve patients maintained CD4500 beyond 12 ART Start: 194 (91%) Initiated ART - 146 (68.5%) within 7 days months. - Same day (34.7%); next day (11.3%); within 7d (22.5%) 9 What’s New in Acute HIV Infection? Le T, et al. NEJM 2013 10 What’s New in Acute HIV Infection? Hoenigl M, et al. Scientific Reports 2016; Little, unpublished data ART Outcomes in AEH Participants (<70d) Universal What’s New in Acute HIV Infection? Variable ART Modified RAPID Jul 2014- Jul 2016- Enrollment period 2009-2013 Jun 2016 Present Rapid ART – how early is early enough? N 162 38 38 Post-treatment control – is it real? Started ART; n (%) 111 (68.5) 35 (92.1) 36 (94.7) Using molecular epidemiology to interrupt Presentation to ART; med days (IQR) 62 (34,142) 12 (8,20) 5 (1,8) transmissions during recent infection EDI to ART; med days (IQR) 105 (66,180) 34 (22,79) 24 (17,75) ART to VL suppression; med days (IQR) 84 (30,169) 55 (28,98) 30 (27,84) 11 What’s New in Acute HIV Infection? Little, San Diego PIRC, unpublished data 12 Post-Treatment Control (PTC) PTC Pooled Analysis: 700 participants/14 studies PTCs identified from 14 clinical studies: - 8 ACTG studies (A371, A5024, A5068, A5102, A5130, A5170, A5187, and A5197) - Montreal Primary HIV Infection Cohort (Montreal PIC) - Seattle Primary Infection Program (SeaPIP) Red=Early-treated - UCSD Primary Infection Cohort (UCSD PIC) Blue=Chronic-treated - UCSF OPTIONS study - NIH therapeutic vaccine trial (NIH) - Ragon HIV Controllers cohort (Ragon) PTCs –Treatment interruption (TI) and subsequent maintenance of VL 400 copies/mL for 2/3 of the time points for 24 weeks. PTCs compared to non-controllers (NCs) who did not meet the PTC criteria. 13 What’s New in Acute HIV Infection? Alter G, et al. IAS Global Scientific Strategy: towards an HIV cure 2016 14 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 Participant Demographics Results Median duration of suppression following TI 89 wks (Q1,Q3: 44,174 wks) PTC more often identified in early- vs. chronic- treated (13% vs. 4%, P<.001) PTC treated during early infection had slightly lower pre-ART VL than NC (4.7 vs. 4.9 log10 RNA copies/mL, P= .09) Transient viral rebound observed in a subset of PTC during first 24 wks after TI, followed by spontaneous viral control - There was no significant difference in the time to peak VL for PTC vs. NC (9 vs. 8 wks) post TI) 15 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 16 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 CD4 Changes post TI (24 weeks) VL Changes post TI (24 weeks) • The median VL peak was lower for PTCs • CD4+ levels generally than NCs (2.6 log HIV RNA copies/mL vs preserved in PTC, but 10 4.7 log10 RNA copies/mL, respectively, P < declined in NC after TI (-32 .001) 3 vs. -221 CD4+ cells/mm , • Similar findings in Early-treated and P < .001) Chronic-treated persons • Similar findings in early- • When VL were measured more frequently treated and chronic-treated (i.e., weekly), 45% of the PTCs had VL persons peaks 1000 HIV-1 RNA copies/mL vs 31% amongst PTCs with less frequent VL sampling (P> .05) 17 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 18 Namazi, et al. JID 2018 Durability of Virologic Control Conclusions Proportion suppressed at: 13% of early-treated and 4% of chronic-treated participants met PTC definition • Year 1: 75% Persons treated during early HIV may have lower barrier HIV remission • Year 2: 55% PTCs relatively stable CD4 during 24 weeks post TI • Year 3: 41% - Durability and magnitude of associated systemic inflammation unknown • Year 4: 30% Many HIV cure study designs involve short analytical treatment interruption • Year 5: 22% (ATI) with ART restarted at some rebound VL threshold. With weekly VL monitoring: ¾ 2 PTC treated during early - a infection maintained durable TI trials that restart ART at VL 1000 copy threshold will miss 50% of PTC - TI trials that restart ART at VL 10,000 copy threshold will miss a33% of PTC suppression > 10 years 19 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 20 What’s New in Acute HIV Infection? Namazi, et al. JID 2018 Sexual Transmission During Recent Infection What’s New in Acute HIV Infection? 1) Montreal: Phylogenetic analysis of transmission chains: Estimated early infection accounted for 49.4% of transmissions1 Rapid ART – how early is early enough? 2) Uganda: Estimated the probability of transmission 49% (27-70) during primary Post-treatment control – is it real? infection (duration 2.90 mo [1.23-6.00])2 3) Malawi: Estimated that early infection gave rise to 38.4% (95% credible interval Using molecular epidemiology to interrupt 18.6-52.3) of transmissions3 transmissions during recent infection 4) Detroit: Estimated that 44.7% (95% CI, 42.2%–46.4%) of transmissions occur during the first year of infection from the population-level viral genetic diversity4 5) Swiss cohort: Estimated 43.7% (range 41-56%) of transmissions occurred during the first year of infection5 21 22 What’s New in Acute HIV Infection? 1Brenner BG, et al. JID 2007; 2Hollingsworth TD, et al. JID 2008; 3Powers KA, et al. Lancet 2011; 4Volz EM, et al. PLoS Med 2013; 5Marzel A, et al. CID 2016 Molecular Epidemiology and HIV Prevention What is an HIV Transmission Network? CDC PS18-1802 Document (2017) - Identifies transmission clusters for Each strain of HIV is unique investigation and intervention Thus, each person’s HIV sequence has a fingerprint-like quality. Priority: Clusters most concerning for recent, rapid transmission and growth that HIV-infected people can be identified as having viruses that are could represent an outbreak. very similar or dissimilar. Clustering at a low genetic threshold (0.5%) consistent with recent This information can be used to estimate the location, direction, transmission rate of spread of HIV within a community. Clusters with at least 5 new cases/cluster diagnosed in last 12 months Generally limit analyses to cases diagnosed the most recent 3-year period If dates of infection are known, transmission direction can be inferred. 23 What’s New in Acute HIV Infection? https://www.cdc.gov/hiv/pdf/funding/announcements/ps18-1802/CDC-HIV-PS18-1802-AttachmentE-Detecting- 24 What’s New in Acute HIV Infection? Investigating-and-Responding-to-HIV-Transmission-Clusters.pdf Defining a Cluster: Using Pairwise Genetic Distance Clustered = Below genetic distance threshold Newly HIV Diagnosed GD<0.02 NT subt/site 25 What’s New in Acute HIV Infection? 26 Wertheim, et al. PLoS Pathog. 2017 What’s New in Acute HIV Infection? Wertheim, et al. PLoS Pathog. 2017 Epidemiologic Linkage Between Two Hosts Public Health Intervention to HIV Hotspots Epidemiologic Linkage Genetic Linkage U1 A B Near real-time phylogenetic monitoring of HIV in British A B Columbia U1 A U B New sequences trigger an automated reanalysis of entire 2 A B database In June 2014, a rapidly expanding cluster was noted U1 A A B - 11 new cases/3 months - including 8 with NNRTI TDR B Enhanced public health follow-up implemented 27 What’s New in Acute HIV Infection? Adapted from Romero-Severson et al. PNAS 2016 28 What’s New in Acute HIV Infection? Poon AFY, et al. Lancet HIV. 2016 Timeline of Cluster 55 Outbreak Limitations No prospective data demonstrating efficacy Potential for false identification and re-identification No consensus approach for defining clusters Variability of sampling coverage - reliability of inferences decrease as sampling coverage decreases Risks of network investigations (esp. directionality) - May disproportionately impact specific communities - Could decrease consumer trust in the medical community New Diagnosis Drug resistance Data sharing has many benefits, but also some risks No resistance 29 What’s New in Acute HIV Infection? Poon AFY, et al. Lancet HIV. 2016 30 What’s New in Acute HIV Infection? Conclusions AHI likely a significant driver of HIV transmission Questions? Same day ART for Acute/Early HIV will rapidly reduce transmission risk and maximize immunologic outcomes Persons treated during early HIV may have lower barrier to achieving HIV remission ATIs in early treated persons could involve peak VLs 10,000 copies/ml Transmission source cannot be definitively determined by genetic data alone. Cluster investigations may provide an important new strategy for HIV epidemic control 31 What’s New in Acute HIV Infection? Disclosures Moving Toward a Cure: Where are • Research support: Gilead, Merck, ViiV We Now? • Consulting: Abbvie, Janssen • SAB: Enochian Biosciences, BryoLogix Steven Deeks, MD Professor of Medicine University of California, San Francisco HIV Cure versus Remission: Cure • Complete removal of all replication-competent PrEP during very early HIV infection (“day 1”) HIV followed by ART resulted in the lack of • No residual stigma (key outcome in surveys) any detectable reservoir • Difficult to achieve and impossible to prove Reservoir size estimated to be ~ 100 replication-competent virions There are now dozens of cases of very low reservoir states in which virus rebounded during an interruption, presumably due to lack of effective immunity HIV Cure versus Remission: Remission • Durable control of a persistent residual reservoir Elite versus post-treatment control • Achieved with “elite” and post-treatment control • Is a remission an improvement over ART? The very curious differences between –Inflammation persists in many controllers these two clinical phenotypes Post-treatment control: Case • 30 year old mixed race (African American/Native American) man • Some (10% to 20%) of people who start therapy early (but not too early) and remain on therapy for years will exhibit at least partial control after • 2011: Presents with acute/recent infection and a viral ART is interrupted load of 10 million copies RNA/mL • May occur in chronic infection (rare) • No biomarker – Elite control would be unlikely • Mechanism unknown • 2011-2014: Effective ART (TNF/FTC/RPV) • Low reservoir size, low T cell activation • Classic CTL responses low, in contrast to elite controllers • 2014: No ART, continued virus control • Non-cytolytic NK cell responses • Enrichment for certain KIRs Post-treatment controllers and non-controllers have comparable levels of viremia during the acute Frequency of activated CD8+ T (pre-ART) stage cells lower in PTCs than elite controllers Post-treatment control generally associated with lower post- Reservoir level also likely lower interruption peak viral loads, (cause and effect unknown) suggesting ART fundamentally changed disease course Ideal models for an effective HIV remission/cure will likely prove to be post-treatment controllers and rare ”extraordinary” natural controllers • Exceptional, extraordinary and/or extreme elite controllers have been described – Low antibody levels, low reservoir and limited Exceedingly rare clinical phenotypes, inflammation particularly in era of universal ART • Some are close to a “cure” “Elite” control is most consistently associated with HIV-specific CD8+ T cell responses, although other pathways are likely involved All models of durable SIV/HIV remission suggest Protective Class I Alleles that durable control of established infection will B*57, B*27, B*13, B*58 require (1) low disease burden, (2) low Gag-specific degranulation, cytokines CD8+ T Cell Proliferation inflammation and (3) sustained host responses (polyfunctional CD8+ T cells) that are primed, reside in tissues, and target Inhibitory activity (ex vivo susceptible epitopes Perforin and granzyme killing autologous CD4+ T cells) Low PD-1, Vulnerable These same attributes apply to cancer Low CD38 TCR diversity immunotherapy CTLA-4, TIGIT epitopes Polyfunctional Low T reg Public TCR Low IDO CD4+ T cells function HIV Immunotherapy: Decades of experimental research Curing monkeys has have largely failed to identify any promising interventions proven to be relatively Trial Regimen Comment Author/Paper easy ACTG 5068 ALVAC (vCP1452) Intermitting interruptions but not vaccine associated with reduced Jacobson, JID 2006 VL ACTG 5024 ALVAC (vCP1452) + IL-1 0.5 log VL reduction during ATI Kilby, JID 2006 ACTG 5097 Ad5 0.24 log10 Schooley, JID 2010 MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have induced early failure Papagno, AIDS 2011 Bionor p24 peptide mixture (Vacc-4x) ATI: no VL effect at primary endpoint, mild benefit at later time Pollard, Lancet HIV points 2014 ERAMUNE 02 DNA prime/MVA boost No effect (HIV DNA) Achenbach, Lancet HIV 2015 GeneCure Replication-defective HIV with Reduced VL set-point (compared to historical data) Tung, Vaccine 2016 VZV fusion protein (HIVAX) GeoVax DNA prime/MVA boost (virus-like No apparent effect during ATI (uncontrolled) Thompson, PLoS particles) ONE 16 ACTG 5281 Gag/Pol, Nef/Tat/Vif/Env and IL- Minimal CD4 effects, no CD8 effects, low dose IL-12 better than Jacobson, JAIDS 12 plasmids (Profectus) high dose IL-12 2016 BCN 02 ChAdV63.HIVconsv + 5/13 controlled (ATI) Mothe, CROI 17 MVA.HIVconsv Immunotherapy for HIV infection T cell immunity: Therapeutic approaches Two decades of largely failed approaches • Weak immunogenicity • Gene modification of stem cells (Berlin Patient) Most likely to – Pre-existing immuno-dominant responses work – CTL escape • CAR-T cells • Inflammation and counter-regulatory • Broadly neutralizing antibodies (immune immunosuppression complexes and the “vaccinal” effect) • Therapeutic vaccination Most • High virus burden scalable – Proof-of-concept: herpes zoster vaccination, • Immune-privileged tissues sanctuaries clearance of pre-cancerous lesions (HPV) Vaccine (Ad26/MVA prime- boost) alone had minimal effect Combination bNAbs after a on reservoir treatment interruption maintained virus suppression Vaccine + TLR7 agonist reduces reservoir during ART Two of 9 individuals treated early maintained virus control and controls SIV post-ART after bNAb levels waned, consistent with a “vaccinal” Vesatolimod now being tested effect in phase I/II clinical trials Immune dysfunction – as quantified by measuring frequency of so- Therapeutic vaccine program (UCSF) “activated” T-cells or inflammation in lymph nodes - persists during long-term ART • HIV DNA (Inovio): RCT enrolling • CMV/HIV vaccine: Funding secured; waiting for GMP product and phase I data in HIV uninfected population • RNA vaccine (CureVac): Dose-escalation study in development; UO1 submitted • Conserved element DNA prime/MVA boost with combination bNAbs: Five-stage combination study recently approved (IND 18488) HuntetalJID2003,PLoS ONE2011andunpublished Hsue etal,JAMACardiology,2017 Inflammation and HIV persistence (and cancer) Immunotherapy and vaccine adjuvant program (UCSF) Pilot (“probe”) studies • Many factors contribute to an inflammatory environment during treated HIV disease • Nivolumab/pembrolizumab (anti-PD-1): Safety studies (cancer) – Microbial translocation, CMV, obesity/life-style, others ongoing; vaccine combination study in development • Inflammation stimulates a potent and sustained immunosuppressive response • Nivolumab/vaccine: Will PD-1 blockade enhance vaccine – Immune checkpoint receptors responsiveness (priming) and provide immediate response to rebounding virus? RCT in development (Lewin/DARE) – Myeloid-derived suppressor cells – T regulatory cells (TGF-ȕ, IL-10) • Vesatolimod (TLR7 agonist): RCT in viremic controllers nearly –IDO completed (Gilead) • IL-15: Follicular disruption pilot study in development Interventions that reduce (Schacker/DARE) inflammation or the counter- • Lefitolimod (TLR9 agonist): Five-stage combination study recently regulatory immunosuppression might approved (IND 18488) be beneficial Immunotherapy and vaccine adjuvant program (UCSF) Reduce inflammation/proliferation • Sirolimus: Study completed (ACTG); data analysis pending • Everolimus: Study completed (transplant population) Perspectives on the “state of the • Canakinumab: Pilot safety study completed; RCT on hold art” in cure research and potential roadmaps for future success My own perspectives 1 My own perspectives 2 Cure versus remission It is all about the timing • A true cure will be difficult if not possible • Most immunotherapies need to be primed and expanded and ready to pounce once the virus • Even if one is cured, you can never be sure begins to replicate (proving a negative is impossible) • A period of controlled viremia (or strong LRA) may –Long-term sustained T cell responses for protection be needed to induce effective CTL, with effector • Super-infection: if PrEP is needed, going from cells delivered to lymphoid tissues at about Week 2 three drugs to two drugs is not adding much of a standard interruption value My own perspectives 3 My own perspectives 4 Reservoir size is too large In absence of a biomarker, only an ATI is interpretable • Natural controllers and post-treatment controllers: reservoir • Scientific and community engagement and support at least 2 logs lower than in typical infection • Legitimate informed consent • Early ART, gene modification strategies, LRAs, anti- • Avoid coercement proliferative drugs might reduce reservoir and all are in the • Mitigate against risk clinic • Exclude those with low nadir, history of cancer/CAD • High baseline CD4+ T cell count – Block and lock might help • Age limits – Long-term ART may also be sufficient • Partner engagement (PrEP) • Strick restart criteria for sustained viremia My own perspectives 5 My own perspectives 6 Product profile You learn by doing • The preferred product profile needs to be defined now • Deep investment exists in basic discovery and pre-clinical models, particularly animal models • This requires a precise discussion on why a cure is needed • Most animal models designed to show an effect of – What will be the unmet need in 15 to 20 years? intervention; parameters set are rarely relevant to typical HIV-infected person – Should the cure be designed to have a global impact now, or should a profitable approach to be used in resource rich regions • Single therapies may not show anything yet still ultimately be pursued, with the hope that in be made available globally? be of value • Scalability will be needed for a full impact – Multiple combination studies using available agents that are safe – Vaccines and bNAbs are attractive and can be rationally done should be pursued My own perspectives 7 Immune- Combination approaches modifying Agents Sanctuary Adjuvants • Given multiple known barriers, combination Disruption approaches will almost certainly be needed – Escape, immunodominance, dysfunctional T cells, chronic inflammation, low antigen exposure on target cells, sanctuaries Therapeutic HIV Low Vaccine Remission • Single arm studies might fail in change any Reservoir biomarker yet prove critical in a combination approach Combinatorial therapy with a therapeutic conserved element DNA/MVA vaccine strategy, a TLR9 agonist and broadly neutralizing antibodies: A pilot study aimed at inducing an HIV remission (IND 18488) Combinatorial therapy with a therapeutic Vaccine conserved element DNA/MVA vaccine adjuvant (TLR9 agonist) Reservoir strategy, a TLR9 agonist and broadly Vaccine boost reduction (MVA) neutralizing antibodies: A pilot study (bNABs/TLR9) aimed at inducing an HIV remission Therapeutic vaccine HIV Enhanced CTL Remission (ATI/bNAbs) (CE DNA) Combinatorial approaches towards and HIV remission IND approval pending Translating NHP success stories using available agents Study on track to open in early 2019 • Stage 1: DNA prime (p24 conserved elements, p24CE) • Goal: induce responses to subdominant, conserved epitopes • Stage 2: DNA boost (p24CE and full-length p55) • Goal: boost CE responses and increase breadth • Stage 3: MVA boost (gag/pol/env) • Goal: boost CE response and increase breadth • Stage 4: bNAbs (10-1074 and VRC07-523LS) and TLR-9 agonist • Goal 1: expand T cell responses • Goal 2: include NK cells, reverse latency ( “shock and kill”, reservoir reduction) • Stage 5: ATI with bNAbs • Goal: induce T cell response (vaccinal effect) SCOPTIONS-CIL-LCV-ASB Platform 'LVFORVXUHV +,93UHYHQWLRQ +RZ$UH:H'RLQJ $QG:KDW¶V2QWKH+RUL]RQ" ,KDYHEHHQWKH3ULQFLSDO,QYHVWLJDWRURQ VWXGLHVIRUZKLFK*LOHDG6FLHQFHVKDVGRQDWHG VWXG\GUXJ 6XVDQ%XFKELQGHU0' &OLQLFDO3URIHVVRURI0HGLFLQH (SLGHPLRORJ\ 8&6) 'LUHFWRU%ULGJH+,9 6)'HSWRI3XEOLF+HDOWK ŝĂŐŶŽƐĞƐŽĨ,/s/ŶĨĞĐƚŝŽŶĂŵŽŶŐĚƵůƚƐĂŶĚĚŽůĞƐĐĞŶƚƐ͕ 4XHVWLRQV ďLJdƌĂŶƐŵŝƐƐŝŽŶĂƚĞŐŽƌLJ͕ϮϬϭϳͶhŶŝƚĞĚ^ƚĂƚĞƐĂŶĚϲ ĞƉĞŶĚĞŶƚƌĞĂƐ Eсϯϴ͕ϲϰϬ :KDW¶VWKHFXUUHQWVWDWHRIWKH86DQGORFDO HSLGHPLF" +RZDUHZHGRLQJZLWK3U(3 DQGZKDWFDQ ZHGRDERXWLW " $UHPLQGHUDERXW8 8 :KDW¶VXSZLWKORQJDFWLQJ3U(3DJHQWV" EŽƚĞ͘ĂƚĂĨŽƌƚŚĞLJĞĂƌϮϬϭϳĂƌĞĐŽŶƐŝĚĞƌĞĚƉƌĞůŝŵŝŶĂƌLJĂŶĚďĂƐĞĚŽŶϲŵŽŶƚŚƐƌĞƉŽƌƚŝŶŐĚĞůĂLJ͘ĂƚĂŚĂǀĞďĞĞŶƐƚĂƚŝƐƚŝĐĂůůLJĂĚũƵƐƚĞĚ ƚŽĂĐĐŽƵŶƚĨŽƌ ŵŝƐƐŝŶŐƚƌĂŶƐŵŝƐƐŝŽŶĐĂƚĞŐŽƌLJ͘͞KƚŚĞƌ͟ƚƌĂŶƐŵŝƐƐŝŽŶĐĂƚĞŐŽƌLJŶŽƚĚŝƐƉůĂLJĞĚĂƐŝƚĐŽŵƉƌŝƐĞƐůĞƐƐƚŚĂŶϭйŽĨĐĂƐĞƐ͘ :KHUHDUHZHLQYDFFLQHGHYHORSPHQW" Ă,ĞƚĞƌŽƐĞdžƵĂůĐŽŶƚĂĐƚǁŝƚŚĂƉĞƌƐŽŶŬŶŽǁŶƚŽŚĂǀĞ͕ŽƌƚŽďĞĂƚŚŝŐŚƌŝƐŬĨŽƌ͕,/sŝŶĨĞĐƚŝŽŶ͘ 1HZ+,9'LDJQRVHVLQ86060 1HZ+,9'LDJQRVHVLQ86 :RPHQ 7UHQGVLQ+,9LQ6DQ)UDQFLVFR 7UDQVJHQGHUZRPHQDQGPHQ /LYLQJ+,9FDVHV 1HZ+,9GLDJQRVHV 'HDWKV +,9UHODWHG'HDWKV 2IQHZ+,9GLDJQRVHVLQWUDQVJHQGHU SHUVRQVLQ 1XPEHURI/LYLQJ&DVHV ZHUHLQWUDQVJHQGHUZRPHQ ZHUHWUDQVJHQGHUPHQ 7UDQVJHQGHUZRPHQKDYHWKHKLJKHVW+,9 SUHYDOHQFHRIDQ\JURXS (VWLPDWHGRI7*:DUHOLYLQJZLWK+,9 1XPEHURI1HZ+,9'LDJQRVHV'HDWKV %XWRI$IULFDQ$PHULFDQ7*:DUHOLYLQJZLWK +,9 ϲϬ Ĩ͘ ƐŝĂ tŽŵĞ Wt/ D^DͲ ,ŽŵĞůĞƐƐ ŵ͘ Ŷ Ŷ Wt/ ϱϬ +RZDUHZHGRLQJZLWK3U(3 ϰϬ DQGKRZFDQZHLPSURYH " ϯϬ ϮϬ ϭϬ Ϭ ϮϬϭϮ ϮϬϭϯ ϮϬϭϰ ϮϬϭϱ ϮϬϭϲ ϮϬϭϳ 6PDOOGHFUHDVHLQSODVPD7)9)7&LQ 7UDQVJHQGHUZRPHQRQKRUPRQHWKHUDS\ +HQGUL[532$ D^D D^D ,ĞƚĞƌŽ ^ ,ĞƚĞƌŽ D^D tŽŵĞŶ;ŐĞůͿ tŽŵĞŶ tŽŵĞŶ DĂLJŵĞĂŶd'tƐŚŽƵůĚĂĚŚĞƌĞƚŽĚĂŝůLJd&ͬ&d͖ŶŽĞĨĨĞĐƚŽĨWƌ WŽŶŚŽƌŵŽŶĞƐ 3U(3ZRUNVDWDSRSXODWLRQOHYHOWRR +,9,QFLGHQFHLQ3HUVRQV8VLQJ7589$'$IRU+,9 6DPHGD\3U(3LQLWLDWLRQLVIHDVLEOH 3U(3 :RUOGZLGH([SHULHQFH)URP6WXGLHV ZLWK32&WK JHQ+,9WHVWRQO\ SHUVRQVRQ 2EVHUYDWLRQDOFRKRUWVWXG\RI3U(3XVHUVWRPRQLWRUUHQDOIXQFWLRQ ϭ͘ϴ DVPHDVXUHGE\H*)5LQSHRSOHZLWKVDPHGD\3U(3VWDUW 3U(3IRU!PRQWKV ϭ͘ϲϮ ϭ͘ϲ LQFLGHQWLQIHFWLRQV ϭ͘ϰ ! 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JonathanVolk,MDMPH InfectiousDiseases KaiserPermanente,SanFrancisco AssistantClinicalProfessor,UCSF SusaCoffey,MD ClinicalProfessor UCSFDivisionHIV,InfectiousDiseasesandGlobalMedicine CoͲLeadWard86RAPIDProgram Chair,GettingtoZeroRAPIDCommittee AudienceResponse:PrEP CASE1 • 8/2016:27ͲyearͲoldMSM,1Ͳ2partners/month DoyoucurrentlyprescribePrEP? foranalsex,usescondoms“someofthetime.” – PrEPoffered,butptdeclinedbecauseofhisconcerns a) Yes,andIonlyprescribedailyPrEP. aboutosteopenia/osteoporosisandlongͲtermside b) Yes,andIprescribebothdailyandonͲdemand effects PrEP. c) Yes,IonlyprescribedailyPrEP,butfor patientswhowanttouseonͲdemandPrEP,I • 8/2018:Seenagaininclinicafter3rd PEPinlast2 advisethemhowtodoso. years. d) No,IdonotprescribePrEP. – TreatedforrectalNGMarch2018 – WillingtotakeTDF/FTCbuthesitanttotakedailymed AudienceResponse:CASE1 WHATISPrEP? Whatwouldyoudonext? • Truvada:Emtricitabine/Tenofovir a) ContinuetoprescribePEPasneeded – FixedͲdosecombinationtablet – FDAapprovedforPrEP in2012 b) StartdailyTDF/FTCafterPEPandencourage • HIVͲnegativeindividualsbefore exposureonadailybasis dailyuse – PrEP1.0 c) StartonͲdemand(2:1:1)TDF/FTCafterPEP • Alternatedosing(2/1/1),otheroralagents(TAF/FTC),longͲ actinginjectables,bNAbs,implantableTAF/CAB,intravaginal d) StartdailyTAF/FTC rings,vaginalandrectalgels,rectaldouches,fastͲdissolving e) CallthePrEP/PEPClinicianConsultation filmsandinserts Center,855Ͳ448Ͳ7737. – CDCestimates~1.2millionpeoplemaybenefit • 310KcurrentlyonPrEPgloballyasofQ12018 6 CDCClinicalPracticeGuidelines,2014;Grantetal.2014;Smithetal.MMWR.2015;Fitchetal.HIVR4POctober2018. PrEPWORKSINTHE“REALWORLD” ISITREALLY99%EFFECTIVE? DatafromKPNorthernCalifornia • iPrEx: – 42%Ͳ datafromtrial 50% – 92%Ͳ detectabledrug 42% – 99%Ͳ modelingdata 5104personͲyears • 76%for2/week • 96%for4/week ofPrEPuse! users 27% 26% • 99%for7/week 23% PrEP of • AdherencedoesNOT needtobe % perfectforMSM 7% 0% 0% • Lessforgivenessforwomen AnySTI RectalSTI Chlamydia Gonorrhea Syphilis HIV – lowervaginaldruglevels IncidentSTIsduringfirstyearofPrEPuse – 6Ͳ7doses/weekmaybeneeded Grantetal.NEJM.2010.;AndersonPL.Sci Transi Med.2012.Grantetal. JuliaLMarcus,LeoBHurley,CharlesBradleyHare,DongPhuongNguyen,Tony 8 LancetInfectiousDiseases.2014;Grantetal.AIDS.2015;29:331–337. Phengrasamy,MichaelJSilverberg,JulietEStoltey,JonathanEVolk,JAIDS2016. INTERMITTENT(SexͲDriven)iPrEP: MOREONͲDEMANDPrEPQUESTIONS 2BEFORE • WhatifapatientmissesapostͲsexdose? & 2AFTER – StartdailyTDF/FTCx28daysvs.3drugPEP • Whoisthe“ideal”onͲdemandPrEP candidate? • Reductioninincidence: Ͳ 86%inRCT&97%inopenͲlabelstudy – Sexualfrequencyandplanningcritical • OpenlabelPrEPStudy(Prévenir): Ͳ OnͲdemand(54%)– noinfectionsin506personͲyears • Whattypeofmonitoringisneeded? Ͳ Daily(46%)–noinfectionsin443personͲyears Molinaetal.NEJM.2015;MolinaAIDS2016;MolinaIAS2018. PrEP FOLLOWͲUP CASE1 • SamefollowͲupforonͲdemand&daily Whatwouldyoudonext? a) ContinuetoprescribePEPasneeded • Every3monthfollowͲup – Rx#90 – HIV b) StartTDF/FTCafterPEPandencourage – Creatinine dailyuse – HepCscreeningwithALT • NotinCDCguidelines c) StartonͲdemand(2:1:1)TDF/FTCafterPEP – STDs:urine/throat/rectalNG/CT&syphilis (recommended) d) StartdailyTAF/FTC • MorefrequentSTDtesting,ifdesired e) CallthePrEP/PEPClinicianConsultation • Annual Center,855Ͳ448Ͳ7737. – HepatitisCantibody – Urinalysis CASE2:NOGREATOPTIONS AudienceResponse:Case2 • 53ͲyearͲoldMSM,PMHnotableforCKD&bipolardisorder Whatdoyourecommendforthispatient? – NumerousrecentSTIs – ~300partnersinprior6months.Asmanyas8partners/day, a) StopPrEPwithFTC/TDF Ͳ contraindicatedwithhis usuallyoralsex,butalsobottoming+/Ͳ ejaculation. kidneyfunction b) Continuean“onͲdemand,”sexͲdrivendosingof – StarteddailyPrEP in2016.HashadworseningCrCl. FTC/TDF – Started“onͲdemand,”sexͲdrivenPrEP dosingstrategy9/2016: • Useswhenheplansonhavingcondomless receptiveanalsex(~3Ͳ c) StartdailydosingwithFTC/TDF withveryclose 4/month) renalmonitoring • DoesnotusewithHIV+undetectablepartners&partnersonPrEP d) StartrenallyͲdosedFTC/TDF witheveryotherday • Doesnotusewithoralsex dosing • Usuallyusescondomswithunplannedreceptiveanalsexwithpartners whoarenotonPrEPornotundetectable e) StartdailyFTC/TAF – HIVAg/Abnegative,CrCl ~25mL/min PrEP&RENALSAFETY CANWEUSETAF/FTC? • PrEPassociatedrenaldysfunctionrare(<1%)intrials • Guidelinesrecommendcreatininemonitoringevery6 monthsduringPrEP(KP:3monthsatmostfacilities) • Renalsafetyinclinicalpractice – Low risk if baseline eGFR 90 at baseline or <50 years old – Only 5/972 patients stopped PrEP indefinitely as a result of decreased eGFR Marcusetal.,JAIDS,December2016 CASE2 CASE#3 Whatdoyourecommendforthispatient? • 23yearͲoldBlack,bisexualtransgenderwoman a) StopPrEPwithFTC/TDF Ͳ contraindicatedwithhis – Receptiveanalsexwithmalepartners(~5Ͳ kidneyfunction 10/month);norecentfemalepartners b) Continuean“onͲdemand,”sexͲdrivendosingof – Condoms~90%ofthetime&usuallyplanssexual FTC/TDF encounters c) StartdailydosingwithFTC/TDF withveryclose renalmonitoring – Noalcohol,occasionalrecreationalMJ d) StartrenallyͲdosedFTC/TDF witheveryotherday – Rectalchlamydia1monthpriortointakevisit,more dosing remotehistoryofsyphilisandgonorrhea e) StartdailyFTC/TAF AudienceResponse:CASE#3 PrEPFORTRANSGENDERWOMEN A)DonotrecommendPrEP.Thereisinsufficient • WorldwideHIVprevalence19.1% datafortransgenderwomen – ORforHIVinfection49(95%CI21Ͳ76)inmetaͲanalysis) B)StartdailyTDF/FTC • 339transgenderwomeniniPrEx analysis • 11HIVinfectionsintxarm&10inplaceboͲ HR1.1(95%CI C)StartonͲdemandPrEPwithTDF/FTC 0.5Ͳ2.7) • NonewinfectionsamongtransgenderwomentakingPrEP,but drugdetectableinonly18% C)Startdailyor onͲdemandPrEPwithTDF/FTC dependingonpatientpreference Baral etal.LancetID.2013;DeutschBMetal.LancetHIV.November2015;Escudero etal.AIDSCare.2015 PrEPFORTRANSGENDERWOMEN CASE#3 • PrEPuptakebarriers–sideeffects,lackof A)DonotrecommendPrEP.Thereisinsufficient transgenderͲinclusivePrEPpromotion,medical datafortransgenderwomen mistrust,prioritizationofhormoneuse • Areasforimprovement: B)StartdailyPrEPwithTDF/FTC – MeaningfulPrEPmessaging – EvidencebasedHIVpreventioninterventions C)StartonͲdemandPrEP – Genderdiscrimination,transphobia,violence – Concernsre:RxͲRxinteractionswithPrEP&hormones • TDF/FTClevelsmaybelowerinseƫngofhormones(љ20Ͳ C)Startdailyor onͲdemandPrEPwithTDF/FTC 27%),butNOimpactonEstrogenlevels dependingonpatientpreference • LargerwellͲcontrolledDDIstudyofestrogenneeded Hiransuthikul,IAS.2018.Hendrix,HIVR4P.2018. DISPARITIESINPrEPUPTAKE 50% HIVseroconverters MoreCasesinPrEPMedicine PrEPusers 40% 38% Drs MatthewSpinelli&SulggiLee 30% 26% 24% patients 1:30PM–BreakoutB 20% of 20% % 12% 10% Ͳ PrEPfailures/resistance 4% 2% 2% Ͳ PrEPandSTIs 0% Ͳ HIVdiagnosticsinsettingofPrEPuse NonͲHispanicBlack Hispanic Age<30 Female Ͳ MoreonͲdemandPrEP Marcusetal,AmJPublicHealth,October2016. RAPIDCase1:StartingRAPIDART RAPIDCase1(2) withoutGT • PE:Afebrile – Largetonsils;LNupto.5cmACandPCbilat • 24yo AsianMSM(immigrant),testedHIV+atSFSTD clinic;referredandseenbyRAPIDnextmorning • Baselinelabssent(HIVAg/Ab,HIVVL,CD4,genotype, • Testedregularly,q2Ͳ3months,lastHIVnegative12 HLAB5701,etc) weeksbefore • Counseling,education • ARTstarted:DTG+TAF/FTCͲ 1st doseinclinic,gave • Sexonlywithmenwhowere“HIVnegative”and“on starterpack,prescriptionssenttopharmacy PrEP” • SWfollowedclosely;MDappointmentin1week – PatientneveronPrEP – CondomlessARIwith3partnersinprevious3months – BaselineCD4361/28%,VL4,142,GT:WT – 12dayslater:VL<20 • Ptengagedwellincare StartingRAPIDARTwithoutGT StateofRAPIDART,2018 ARVsforRAPID • ImmediateARTisstandardofcareat • Highgeneticbarriertoresistance Preferred: • Potentathighviralload • Dolutegravir+TAF/FTC UCSF/SFGHWard86andinSanFrancisco Reasonable: • • Promotedby2018IASͲUSAGuidelines Simple,tolerable,easytotake • (Bictegravir +TAF/FTC) • Availablethroughpt’s insurance • Darunavir/booster+ – “ARTshouldbeinitiatedassoonaspossibleafter TAF/FTC diagnosis,includingimmediatelyafterdiagnosis, Donotuse Otheroptionspossible unlesspatientisnotreadytocommittostarting therapy….” • Abacavir(requiresHLAB5701testing) • NNRTIs(transmittedresistance) • Considered“investigational”byDHHS Guidelines CanchangeARVs,ifindicated,afterGTresultsavailable Case2:WhattodoͲ PrEP orRAPID? RAPIDCase2Ͳ ARS • 33yo AAMSMpresentstoclinicforPrEP Whatwouldyoudoatthispoint? • Severalpartnersinpast2months – condomlessreceptiveanalsexwithHIV+partners A. WaitforHIVviralloadresultsbeforestarting whosaidtheywere“undetectable”onARVs anymedications • RapidHIVtest:negative B. StartPrEP – HIVRNAsent C. StartPEP • Notedfever,sweats,throatdiscomfort D. StartART beginningdayofpresentation RAPIDCase2(2) RAPID:PotentialBenefits • HewasstartedonPrEP:TDF/FTC • Reduce risk of HIV complications • 1weeklater,HIVRNAresultreceived:3million • For acute/early HIV, decrease the size of the HIV reservoir • Reduce HIV transmission • ReferredforRAPIDART • Early linkage to care – Reported1weekoffevers,sweats,fatigue,headache, sorethroat,myalgias,abdominalpain,7lb weightloss • May increase retention • May help empower patient • Patient expectation • Note:duringpastweek,hadcondomlessanalsex with2partners RAPIDCase2Ͳ ARS RAPIDCase2(3) WhatARTwouldyoustart? • Starteddolutegravir+boosteddarunavir+ TAF/FTC(concernforresistancetoFTCor/and A. Dolutegravir+TAF/FTC TFV) B. Bictegravir/TAF/FTC C. Darunavir/cobicistat/TAF/FTC • Genotyperesult:K103N,M184I D. Dolutegravir+boosteddarunavir+TAF/FTC • HIVviralloadsuppressedin<2months,ART simplifiedtodolutegravir+TAF/FTC 27yo man,HIVviralload3million,onPrEP x 1week,likelyhasacuteHIV.HIVgenotypeis notknown. NewHIVDiagnosesper100,000populationby RAPIDCase1and2takeͲaways race/ethnicity,SanFrancisco • ScreenforacuteHIVssx,startARTforsuspectedARS(not PrEP!) Men Women • RAPIDARTforearliereffectontransmissionrisk,aswellas individualhealth • RAPIDARTregimensmustcoverpossibilityofveryhighHIV viralload,moderatedrugresistance • PreventionstrategiesforHIVͲnegative individualsmaybe DIFFERENTthanstrategiesforHIVͲpositive– cautionrerelying onpartners’reportsofHIVnegativestatus,PrEP,ART • (DisparitiesinwhogetsHIV,whohasaccesstoPrEP) SFDPHHIVEpidemiologyAnnualReport2017 Case3:RAPIDARTinWomen RAPIDCase3:ARS • 19yo whitecisgenderwoman,testedatacollegeclinicafter BFtestedpositiveforHIV WhatARTwouldyoustart? – Testresults:HIV+(Ag/Ab+,diff+) • ScheduledforRAPIDintakethenextday • BelievedshewasHIVnegativeapprox 9monthsearlier (recordslaterobtained:lastHIVneg nearly2yrs earlier) A. Dolutegravir+TAF/FTC • 1regularmalepartner,“openrelationship;”sexwithmenand B. Bictegravir+TAF/FTC women;occasionalecstasy,GHB; noinjectiondruguse • Contraception:OCPs C. Darunavir/cobi/TAF/FTC • NorecentARSsx D. Somethingelse – 1yearearlierhadERvisitfor1weekoffever,headache,myalgias, pharyngitis,recentmacularrash.HIVtestnotdone. RAPIDCase3(2) RAPIDCase3(3) ARTstarted(1st doseinclinic+starterpack+ Dolutegravir:concernforelevatedriskof prescription neuraltubedefectsininfantsborntowomen • BaselineCD4229/14%,VL429,000,GT= takingdolutegravirattimeofconception wildtype • DHHS:Forthosewhoareusingeffective contraception,aDTGͲbasedregimencanbe consideredafterweighingtherisksandbenefitsof • 6weekslater,VL=63c/mL,<40soonafter DTGusewiththeindividual that Bictegravir:nodatainpregnancy. • Sometimesmissesclinicvisitsbutrelatively wellconnected,esp viatextmessaging Case4:HIVtestinterpretationcanbetricky RAPIDCase3:Takeaways (forprovidersand patients) • 37yo Latinx MSMpresentedtoSFGHERwith1Ͳ2daysoffever(100Ͳ • OfftheradarforHIVriskandHIVprevention 101϶),fatigue,nausea,backpain – Eval incl.Monospot,flu,bloodcx,UA,CXR,stool(Shigatoxin,cx,O&P)= • MissedopportunityforearlydiagnosisͲͲ negative – Givencipro x3d recognizeacuteHIV(hadacuteHIVsx 1yr earlier) • ReturnedtoER3dayslaterforpersistentfever,fatigue – Condomlessanalsex1Ͳ2weeksbefore,unknownpartner • Cautionredolutegravirforwomenwhomay – HIVtestsent: • Ag/Abpositive(Architect), becomepregnant • Differentiationtestnegative (Multispot) – HIVRNAordered;patientsenthome • RAPIDteamreceives/reviewsallnewHIV+labreports:calledpatient andbroughthimintoWd 86(sameday) – PreviousHIVtest6Ͳ7monthsearlier,negative – NotonPrEP RAPIDCase4(2) RAPIDCase4(3) • F/u2weekslater • PE:T=98.2(onacetaminophen),tearful,examo/wwnl – TakingARTbutit“isastruggleasitremindsmeofmyHIV” – Intakelabresults(doneonday#5ofART): • StartedDTG+TAF/FTCforsuspectedacuteHIV • CD4525/30%,HIVRNA20,700 st –1 doseinclinic,7daystarterpackandprescriptiongiven • HIVAg/Abnegative –Intakelabscouldnotbedone – Patient:questions(crisis)rewhetherHIVtestresultsare accurate • F/u5dayslater: – MuchSWandMDsupportreimportanceofcontinuingART –VLresultfromER:3.7million –PttakingART;sx greatlyimproved – VL=75after3weeksonART –Mooddistraught–“mydreamsareover;I’llgobackhome • SubsequentHIVAg/Abtests: andlivewithmyfamily.” Test Day1 Day63weeks 11weeks –Intakelabssent,withrepeatHIVVL,Ag/Ab Ag/Ab Reactive Nonreactive Nonreactive Reactive Differentiation Negative Negative HIVRNA 3.73 20,735 75 ND million RAPIDCase4:TakeAways SanFranciscoRAPID:Shortenedtimeto care,ART,andHIVvirologicsuppression • Testinterpretationcanbequitechallenging(seek expertconsultation) Metric 2013 2014 2015 2016 • Explainingtopatientsmaybeevenharder! MedianDays Diagnosisto1st carevisit 8 7 7 5 • RAPIDmeansARTmovestothefirstvisit,butall CaretoART 27 17 7 1 theusualHIVeducation,counseling,andsupport ARTtoVL<200 70 53 50 38 (sometimesmore)mustaccompanyandfollow DiagnosistoVL<200 134 92 77 61 ARTstart! • Callforconsultation Baconetal,CROI2018,Abs.93 RAPIDResources www.getting tozerosf.org Referral/Consultation:SFGH Ward86HIVTesting/Linkage toCare(PHAST/RAPIDteam) Pager:415Ͳ443Ͳ3892(MͲF,8Ͳ5) https://hividgm.ucsf.edu afterhours:VM415Ͳ206Ͳ2460 Goals •WorkingproficiencyinselectinginitialARTregimens AntiretroviralTherapyInitiation: •ReviewDHHSfirstline&alternateregimens –Prosandcons,considerations,choices FromGuidelinestoPractice:ART101 –Manyupdatesfromlastyear(4newdrugsFDAapprovedin2018) •Willnotfocuson: –InǦdepthARTpharmacology MedicalManagementofAIDS&Hepatitis –HIVdrugresistance December6,2018 – OptimizingARTregimensinvirallysuppressedindividuals –2ǦdrugorNucleosideǦsparingregimens –ARTforpediatricorpregnantpatients VivekJain,M.D.,M.A.S. –DrugsindevelopmentbutnotyetFDAapproved AssociateProfessorofMedicine DivisionofHIV,InfectiousDiseases&GlobalMedicine •45minutes…lotstocover! SanFranciscoGeneralHospital,UniversityofCalifornia,SanFrancisco Disclosures USDHHSGuidelines:1st LineTherapy Yellow=October2018updates • ResearchgrantsupportfromNational InstitutesforHealth(NIH),Centersfor DiseaseControl(CDC)&President’s Recommendedregimensarethosewith Theseregimensareeffectiveandtolerable,buthave demonstrateddurablevirologic efficacy,favorable somedisadvantageswhencomparedwiththeregimens EmergencyPlanforAIDSRelief(PEPFAR)– tolerabilityandtoxicityprofiles,andeaseofuse. listedabove,orhavelesssupportingdatafrom randomizedclinicaltrials.However,incertainclinical situations,oneoftheseregimensmaybepreferred. –ForworkongoinginEastAfricarelatedtoHIV caremodels –Thisdisclosureisunrelatedtothispresentation $GDSWHG)RRWQRWHV D 7&PD\EHVXEVWLWXWHGIRU)7&RUYLFHYHUVD$%&7&7')7&7'))7&7$))7&DUH DYDLODEOHDVWDEOHWVDQGDVSDUWRIVLQJOHWDEOHWUHJLPHQV&RVWDFFHVVDQGDYDLODELOLW\RIRI675V FDQLQIOXHQFHFKRLFHRI7&YV)7& E 7$)DQG7')DUHWZRIRUPVRIWHQRIRYLUDSSURYHGE\WKH)'$7$)KDVIHZHUERQHDQGNLGQH\ WR[LFLWLHVWKDQ7')ZKLOH7')LVDVVRFLDWHGZLWKORZHUOLSLGOHYHOV6DIHW\FRVWDQGDFFHVVDUH DPRQJWKHIDFWRUVWRFRQVLGHUZKHQFKRRVLQJEHWZHHQWKHVHGUXJV F 5$/FDQEHJLYHQDVPJ%,'RUPJ WZRPJWDEOHWV RQFHGDLO\ USDHHSARTGuidelines–October28,2018Update http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf U.S.DHHSGuidelineUpdate:October,2018 ARVsinCommonUse,2018 InitialRegimens InitialRegimens NRTI(nucleosideanalogs) ProteaseInhibitors • Tenofovir alafenamide TAF • Darunavir DRV “forMostPeople” “inCertainClinicalSituations” • Tenofovir TDF • Atazanavir ATV BIC/TAF/FTC EVG/cobi +(TDF/FTCorTAF/FTC) •Abacavir ABC • Ritonavir RTV *Ifreproductivepotential,consultguidance *Ifreproductivepotential,consultguidance • Emtricitabine FTC • Cobicistat Cobi • Lamivudine 3TC DTG/ABC/3TC RAL/ABC/3TC OnlyifHLB57Ǧ01negative OnlyifHLAB57negativeandVL<100,000 *Ifreproductivepotential,consultguidance *Ifreproductivepotential,consultguidance NNRTI(nonǦnucleosides) NewFDAApprovalsin2018 DTG +(TDF/FTC orTAF/FTC) (DRV/RTVorDRV/cobi)+(TDF/FTCorTAF/FTC) • Rilpivirine RPV •2/18:Bictegravir BIC •3/18:Ibalizumab:monoclonalAb IBA RAL +(TDF/FTCorTAF/FTC) (DRV/cobi orDRV/RTV)+ABC/3TC •7/18:TAF/FTC/cobicistat/DRV Symtuza OnlyifHLB57Ǧ01negative IntegraseInhibitors •8/18:Doravirine DOR (ATV/cobi orATV/RTV)+(TDF/FTCorTAF/FTC) • Bictegravir BIC Organizationalcomments: •Dolutegravir DTG • BIC/TAF/FTCnewin2018... (ATV/cobi orATVRTV)+ABC/3TC • Elvitegravir EVG •DORaddedtosecondlinein2018... OnlyifHLAB57negativeandVL<100,000 • Raltegravir RAL •DRVmovedoutoffirstlinelistin2017… • EVG/cobi/TAF/FTCandEVG/cobi/TDF/FTC DOR +(TDF/FTCorTAF/FTC) movedoutoffirstlinein2018… •Guidelinesdon’treallyemphasizeTAFvs. EFV +(TDF/FTCorTAF/FTC) TDFmuch… RPV +(TDF/FTCorTAF/FTC) Adaptedfrom:USDHHSARTGuidelines–October28,2018Update OnlyifVL<100,000&CD4+>200 FDAǦApprovedARVs,2018 BasicInitialRegimenComposition NRTI(nucleosideanalogs) ProteaseInhibitors • Tenofovir alafenamide TAF • Darunavir DRV Previously: Currently: • Tenofovir TDF •Atazanavir ATV NNRTI •Abacavir ABC • Ritonavir RTV • Emtricitabine FTC • Cobicistat Cobi • Lamivudine 3TC • Lopinavir LPV EFV RPV • Stavudine D4T • Fosamprenavir FPV INSTI • Didanosine DDI • Amprenavir APV or 2x NRTI • Zalcitabine DDC • Tipranavir TPV • Zidovudine ZDV •Nelfinavir NFV 2x NRTI BIC DTG RAL • Saquinavir SQV PI TAF/FTC NNRTI(nonǦnucleosides) • Indinavir IDV TDF/FTC or • Rilpivirine RPV + or or r/ATV r/DRV • Etravirine ETR CCR5Inhibitors TDF/FTC • Doravirine DOR • Maraviroc MVC + ABC/3TC •Efavirenz EFV or PI • Nevirapine NVP FusionInhibitors or •Delavirdine DLV •Enfuvirtide TǦ20 ABC/3TC r/DRV IntegraseInhibitors MonoclonalAntibody INSTI • Bictegravir BIC • Ibalizumab IBA •Dolutegravir DTG RAL EVG DTG • Elvitegravir EVG • Raltegravir RAL NRTI’s:TDF/FTC(Truvada) TDF/FTC(Truvada):evidencesupportingrenalconcerns? LargemetaǦ analysis Slow,small includingRCTs: smalldifference, magnitude TDF decrement perhaps3Ǧ4 Other mL/mineGFR NRTI’s ineGFR CooperCID2010 overtime? Generalizeddecreaseinrenalfunction Japanesecohortwithlargerdeclinein TDF>Otheragents;differencesmall eGFR withTDFvs.ABC ModestlossinY1,lessafterthat Nishijima AIDS2014 Ǧ10eGFR after6YTDFvs Ǧ9 Laprise CID2013 Issues:controversialtopic •observationalstudyvs.RCT Smallriskof • baselineeGFR proximal Initialcase Aknown •lowbodyweight reports lowǦlevel tubulartoxicity/ 2002Ǧ2004 risk;forms •otherrenalrisks Fanconi’s thebasisof •useofr/PI syndrome? monitoring •othernephrotoxicmeds NRTI’s:TenofovirǦbasedMeds NRTI’s:TDF/FTC(Truvada) TDF/FTC(Truvada):evidenceforboneconcerns? TDF/FTC(Truvada) TAF/FTC(Descovy) HipBMD SpineBMD RenalConcerns BoneConcerns RenalProfile •Decrement inbone densityafter Decreasein Decreasein better? ARTinitiation eGFR over bonedensity? time? BoneProfile •Then stabilization Riskof better? tubular Concomitant ACTG5202Study:McComsey,JID,2011 toxicity/ increase •Clinicalsignificanceofa2Ǧ4%lossofBMDunclear… Fanconi’s riskof LipidProfile syndrome? fracture? •Noapparentevidencethatthistranslatestohigherriskoffracture… worse? NRTI’s:TAF/FTC(Descovy) NRTI’s:TAF/FTC(Descovy) TAF(tenofovir alafenamide) Evidenceforimprovedboneprofile?Æ (Study104/111Datathrough144weeks) •Plasmaconcentrationsare OralTAFprodrug TAFtakenintocells,hydrolyzed/processedtocreate 90%lowerthanTDF circulatesin tenofovir(TFV),thenphosphorylatedtocreate • Intracellular plasma tenofovirǦdiphosphate(TFVǦDP,theactivedrug concentrationsmuchhigher Lessdrop inBMD Smaller riseinPTH Lessdrop Virologic nonǦinferioritytoTDF/FTC inBMD (datathrough144weeks) Genvoya (TAF/FTC/cobi/EVG) noninferior SimilardatafromAMBERStudy: to Stribild (TDF/FTC/c/EVG) • TAF/FTC/cobi/DRV noninferior to (Study 104/111): Arribas J et al., JAIDS, 2017 TDF/FTC+cobi/DRV: Lessdeclineinbonedensitythrough96weeks: • at Week 48: 91% VS [TAF] vs. 88% [TDF] • at Week 48: 92% VS [TAF] vs. 90% [TDF] SimilardatafromAMBERStudy: Eron JJ et al., AMBER Study: AIDS, 2018 Smallerdecreaseinhip bonedensity: • at Week 96: 87% VS [TAF] vs. 85% [TDF] •LessbonedensitydeclinewithTAF: • at Week 144, 84.2% [TAF] vs. 80.0% [TDF] Ǧ0.7% [ECFǦTAF]vs.Ǧ3.3%[ECFǦTDF] (p<0.001) Hip Spine Femneck Similar AE profile, lipid effects D/C/F/TAF +0.21% Ǧ0.68% Ǧ0.26% Smallerdecreaseinspine bonedensity: Week 48 data: Sax PE et al., Study 104/111: Lancet, 2015 D/CTDF/FTC Ǧ2.73% Ǧ2.38% Ǧ2.97% Week 96 data: Wohl D et al., Study 104/111: JAIDS, 2016 Ǧ1.0%[ECFǦTAF]vs.Ǧ2.8%[ECFǦTDF] Week 144 data: Arribas J et al., Study 104/111: JAIDS, 2017 (p<0.001) Eron JJ et al., AMBER Study: AIDS, 2018 NRTI’s:TAF/FTC(Descovy) NRTI’s:TAF/FTC(Descovy) Evidenceforimprovedrenalprofile? Smallerchangesinproteinuriaby4measurements: (Study104/111Datathrough144weeks) •eGFR,urineprot./creat.,RBP/creat.,E2M/creat. Smallerpillsize Compellingforsomepatients; lessimportanttootherpatients LessdeclineineGFR: •mediandropinCrCl: Ǧ2.0mL/min[ECFǦTAF] Ǧ7.5mL/min[ECFǦTDF](p<0.001) TAF/FTC Stribild Fewerdiscontinuationsdueto renaldysfunction: •0discontinuations[TAF] TDF/FTC Genvoya •vs.12discontinuations[TDF] Arribas J et al., JAIDS, 2017 SimilardatafromAMBERStudy: • Less decline in eGFR with DCF/TAF vs. DRV/cobi+TDF/FTC • Smaller changes in proteinuria Eron JJ et al., AMBER Study: AIDS, 2018 Also note: Can use TAF for patients with eGFR30 Sax PE et al., Lancet, 2015, Wohl D et al., JAIDS, 2016, whereas TDF for patients with eGFR60 Arribas J et al., JAIDS, 2017 NRTI’s:TAF/FTC(Descovy) NRTI’s:ABC/3TC(Epzicom) Lipidprofile Druginteractions ABC/3TC(Epzicom): Lipidchangefrombaselineto144weeks Rifamycins ABCHypersensitivity CardiovascularConcerns isworseinTAFvs.TDF: Induce CYP3A4,PǦgp,andBRCP PolymorphismofHLAB57Ǧ01allele Enhancedplateletreactivity? 4Ǧ8%ofoverallpopulationpositive; Theoretical TAF TDF Inhibit OATP1B1,OATP1B3 Basic 2Ǧ4%amongAfricanAmericans basisfor Plateletaggregation? biology PromotesischemicCVdisease? Totalchol. Ï31 Ï13 Neteffectofthisunknown ABCbindstoHLAmolecule, concern triggeringHSreaction Controversial DonotcoǦadministerrifamycins withTAF HDL Ï6 Ï2 • Databasestudiesareequivocal LDL Ï19 Ï6 TAFwithcobicistat •DonotclearlydemonstrateMIrisk Fullydiscriminative HLAǦ TG Ï20 Ï12 TAFasubstrateofCYP3A4,PǦgp,OATP1B1,and B57Ǧ01 IfpositiveÆABC contraindicated OATP1B3 IfnegativeÆABC safe Arribas J et al., JAIDS, 2017 Testing Issues:controversialtopic CobiinhibitstheseÆ boostsTAFlevels •observationalstudiesvs.RCTs Note:TDFassociatedwithfavorable GuidelineLanguage:“Increasein •otherCVrisks:accountedfor? Thus,TAFdosewithcobi is10mgnot25mg CVeventsisassociatedwithABCuse lipidprofile;TAFisamoveawayfrom •risksfromotherARVs? thisfavorableprofile insome,butnotall,cohortstudies” •durationoffollowǦup? •whatoutcomesassessed? TAFandTDFSummary NRTIsforPatientswithHBV TDF/FTC(Truvada) TAF/FTC(Descovy) •ForHepatitisBpositivepatients: RenalConcerns BoneConcerns RenalProfile – TDF/FTC: better? •2activeagents:goodchoice Decreasein Decreasein eGFR over bonedensity? – TAF/FTC: time? BoneProfile •2activeagents better? Riskof •alsoFDAapprovedforHBV+patients;goodchoice tubular Concomitant toxicity/ increase LipidProfile Fanconi’s riskof – ABC/3TC: syndrome? fracture? worse? •onlythe3TCisactive •ifusingABC,typicallycombinewithentecavir ConsidereGFR,proteinuria,osteoporosis, andneedforrifamycins inthisdecision… Integrase InhibitorOverview Dolutegravir (DTG) Tivicay (DTG50mg) •Highlypotent,highly SINGLEStudy:DTG+ABC/3TCvs.EFV/TDF/FTC efficacious •144Ǧweekviralsuppression71%vs.63%(superior) •Highgeneticbarrierto SPRINGǦ2Study:DTG +(ABC/3TCorTDF/FTC)vs. resistance Integrase RAL +(ABC/3TCorTDF/FTC) • 50mgQDdosing,no •96Ǧweekviralsuppression82%vs.78%(nonǦinferior) Inhibitors booster FLAMINGOStudy:DTG+(ABC/3TCorTDF/FTC)vs. • Availableaspartof DRV/RTV+(ABC/3TCorTDF/FTC) Triumeq,orseparately •96Ǧweekviralsuppression71%vs.63%(nonǦinferior) • NeedBIDifusingwith EFV,orwithrifampin IntegraseInhibitors:Overview Dolutegravir(cont’d) •DominantclassofART:goalisforallpatientstobe Notes/Caution: consideredforINSTI •DTGalongonlyforeGFR>30 •SideeffectsÆ discontinuation •DTGasTriumeq onlyforeGFR>50 initiallythoughttobe<2Ǧ3%infirst •Dolutegravircontinuestobeinwideuse •InhibitsOCT2Æ inhibitstubular year Curtisetal.,HIVClin Trials.2014 –PartofsingletabletregimenTriumeq creatininesecretion,ÏCrwillrise • Headache,insomniaincreasingly –Alsoavailableseparately 0.1Ǧ0.3 recognized •15%(85/556)Amsterdampatients • Bictegravir FDAapprovedin2018 •Decreasedabsorptionwhen stoppedDTG: –OnlyavailableaspartofsingletabletBiktarvy polyvalentcationsgiven(Ca+2, 6%(sleep),4%(GI),4%(malaise),3% (psychological) • Elvitegravir (E/C/F/TAF,andE/C/F/TDF) Mg+2,Fe+3,e.g.)Æ spaceDTG2h 2%joint/tendon/muscle,2% –BothGenvoya andStribild movedfrom1st to2nd line beforeor6hafterthese neurologic deBoeretal.AIDS2016 st • Hypersensitivity/skinreactions • Raltegravir remainson1 linelist •Caution:boostsmetforminlevels uncommon(<1%) IntegraseInhibitorOverview(cont’d) IntegraseInhibitors(cont’d) Bictegravir (BIC) Biktarvy (BIC25mg/TAF10mg/FTC200mg) Elvitegravir (EVG) •Highlypotent,highly Trial1489:Biktarvy vs.Triumeq efficacious •48Ǧweekviralsuppression92%vs93% •WellǦtolerated,strong efficacy • Hypersensitivityrare • 150mg QD dosing •VSsimilarinVL<100K,VL100KǦ400Kand •1/866patientshadrashinEVG •Highgeneticbarrierto •Requirescobicistat (150mgQD) VL>400K studies resistance •Lowergeneticbarriertoresistance Stribild (TDF300/FTC200/cobi 150/EVG150) Trial1490:Biktarvy vs.TAF/FTC+DTG • 25mgdoseaspartof Genvoya (TAF10/FTC200/cobi 150/EVG150) singletabletBiktarvy •48Ǧweekviralsuppression89%vs93% (TAF/FTC/BIC) SaxPEetal.,Lancet,2017 Raltegravir (RAL) Gallant,Jetal.,Lancet,2017 Isentress (RAL400BID) Isentress HD(RAL600x2QD) • Nobooster •VerywellǦtolerated,good • Hypersensitivityreaction(rare, potency/efficacy mild) • 400mgBIDdosing •Evenrarer:DRESSsyndrome •Candoseat1200mgQD Ripamonti etal.AIDS2014 (noninferior to400mgBID) • No boostingrequired •Lowergeneticbarriertoresistance Bictegravir (cont’d) IntegraseInhibitorDrugInteractions Cautions: •Therearealotofthese…EVGmostproblematicbecauseofcobi… •DTG,BIC,RALlessproblematic… • Inhibitstubularsecretionof •DonocoǦadministerwithrifampin •Keytoremember(andlookup):antacids,cations(Mg/Al/Ca),metformin, creatinine:raisesCrby (reducesBICandTAF) rifamycins,steroids(dex) 0.1mg/dLOnly foreGFR>30 •NotforliverdiseaseChildǦPughC • Boostsmetforminlevels Dolutegravir Bictegravir Raltegravir Elvitegravir Al/Mg/Ca 2hbeforeor6hafter 2hbeforeantacids Don’tcombinewithAl/Mg Separatefrom •SubstrateofCYP3A:soanyinducer •CautionforpatientswithHBV antacids antacidwithcations withAl/Mg/Ca, antacids… antacidsby>2h ofCYP3AwilldecreaseBIClevels whendiscontinuing:riskofHBV ForCaantacids,onlyuse400 BIDRALdose •ViceversaforinhibitorsofCYP3A flare H2Ǧreceptor Nodoseadjustmentsneeded •Sameforinducerorinhibitorof blockers UGT1A1 •AntacidswithAl/Mg/Ca:takeBIC PPI’s Nodoseadjustmentsneeded 2hbefore •TAFcomponentisasubstrateofPǦ •Fe/Casupplements:takewithBIC gp andBCRP…soinducerscan andfood Mustscreenyourpatientforthese,andgoodtodocument(esp.ifonEVG)inyournotesforothers: reduceTAF,inhibitorscanincrease ”patientonINSTI:consultpharmacyteambeforestartingantacids,anticoagulants,antiepileptics, TAF… antidepressives,metformin,rifamycins,cations,orsteroids.” DolutegravirandPregnancy •Dolutegravirinpreliminary/emergingdatahasbeenassociatedwithlow rateofneuraltubedefects • Guidelines:“preliminarydatasuggestthatthereisanincreasedriskof neuraltubedefects(NTDs)ininfantsborntopeoplewhowerereceiving DTGatthetimeofconception” – “negativepregnancytestresultshouldbedocumentedpriortoinitiatingDTG Protease inantiretroviraltherapy(ART)Ǧnaiveindividualsofchildbearingpotential –DTGisnotrecommendedforthosewhoarepregnantandwithin12weeks postǦconception Inhibitors –DTGisalsonotrecommendedforthoseofchildbearingpotentialwhoare planningtobecomepregnantorwhoaresexuallyactiveandnotusing effectivecontraception –Forthosewhoareusingeffectivecontraception,useofaDTGǦbasedregimen canbeconsideredafterdiscussingtherisksandbenefitsofthisdrugwiththe patient” •ItisnotyetknownwhetherotherINSTIsposeasimilarriskofNTDs(i.e.,a classeffect). IntegraseInhibitorOverview ProteaseInhibitorOverview Dolutegravir Bictegravir Raltegravir Elvitegravir • Darunavir (DRV/r) Frequency QD (ARTǦnaïveorINSTIǦ QD 1200mgQD QD •Highestpotency;fewersideeffectsthanotherPIs;welltolerated naïve) or Norvir:RTV100 Prezista:DRV800 400mgBID BID:withCYP3A4orUGT1A1 • 800mgQDdosing(ifnoDRVmutations) inducers,orwithINSTImutations –concomitantlyadministereitherRTV100mgQDorcobicistat 150mgQD Prezista: DRV600 Genetic High High Lower Lower • 600mgBIDdosing(whenDRVmutationspresent) barrierto –concomitantlyadministerRTV100mgBID(don’tusecobicistat forboosting) resistance Singletablet Yes,Triumeq Yes,Biktarvy No Yes,Genvoya or •Sideeffects:overalllow RTV100 regimen Stribild option? •AswithmostPI’s:GIsideeffects,skinrash(sulfamoiety)– usuallyselflimited, dyslipidemia,rarehepatotoxicity Prezcobix: Keyside Nausea,diarrhea/GIdisturbance,headache,insomnia DRV800/cobi 150 effects •Advisetakewithfood IncreasedCK,myositis, Myositis,increased myositis, hyperlipidemia • UnlikeATV:nohyperbilirubinemia;nospacingapartfromH2Ǧblockers;PPI’sare hypersensitivity, CK(4%) hypersensitivity, ok hepatotoxicity hepatotoxicity, SJS/TEN •Movedfromfirstlinetosecondlinein2017 Symtuza: DRV800/cobi 150/ TAF/FTC TrialDataSupportingD/C/F/TAF • Darunavir/cobi/TAF/FTC(800/150/10/200) – AMBER Study(ARTǦnaïveadults,randomizedto D/C/F/TAF(n=362)vs.DRV/cobi +FTC/TDF (n=363)to W48(doubleblindphaseIIInonǦinferioritytrial,Ǧ10% margin) – D/C/F/TAF:91.4%VSatWeek48vs.DRV/cobi + NNRTI’s TDF/FTC:88.4%VS(+2.7%,95%CIǦ1.6%to+7.1%; nonǦinferior) AMBER: Eron JJ et al., AIDS, July 2018 – EMERALD Ph.3switchstudy(invirallysuppressed adults)alsoshowednonǦinferiormaintenanceofVS withD/C/F/TAFvs.control EMERALD: Orkin, C et al., Lancet HIV, 2017 ProteaseInhibitors(cont’d) NNRTIOverview RTV100 ATV300 • Potency similartoEFV •Lowerefficacywhen • Atazanavir (ATV/r) Rilpivirine (RPV) •LacksCNSsideeffects VL>100KorCD4<200 • Goodpotency,generallywellǦtolerated,300mg QD(+RTV100mgQD) •Lesslipideffects • Requires 400cal.meal •LeasteffectonlipidsofPI’s Edurant:RPV25 •H2blocker:give12h beforeor4hafterRPV • Ĺbilirubin:sometimescosmetic,sometimesbeyond Odefsey:RPV25/ • PPI:avoid •GERD:inARTǦnaïvepatients: TAF25/FTC200 •Insecondlinelist –H2blockers:giveATV400QD 2hbeforeor10hafterH2;giveATV300/RTV100 anytime Doravirine •FDAapproved2018:ARTǦnaïve •Lowratesofheadache, – PPI:useomeprazole20orequivalent(maximum)12hbeforeATV • Goodpotency nausea,diarrhea (DOR) •HasTDFincombinationpill • MetabolizedbyCYP3A; • Recommendtakewithfood Recommendagainst •Don’tcombinewith combiningATVwithPPI Pifeltro:DOR100 •Notinfirstlinerecommendedlist •Pifeltro:Nodoseadjustmentfor rifampin(rifabutinokif renalfailureorliverdisease useDOR100BID) Delstrigo:DOR100/ •Insecondlinelist TDF300/FTC300 • Delstrigo:onlyforeGFR>50 NNRTIOverview(cont’d) SingleTabletCoǦFormulations Efavirenz •Potencywell •Cautionwithdepression NRTI Protease established •Raresuicidality Tenofovir TAF Ritonavir (EFV) •QD •CNSsideeffects:insomnia, Emtricitabine dreams Descovy Atazanavir Sustiva:EFV600 • Lipideffects April,2016 •Insecondlinelist Truvada Abacavir Evotaz Darunavir •PotencysimilartoEFV •BIDdrug(200mgBID) 2004 Etravirine January,2015 •Lesslipideffects (datasupport400mgQD) Epzicom (ETV) •Insecondlinelist 2004 Cobicistat Intelence: Lamivudine ETR200x2 Prezcobix Doravirine January,2015 Raltegravir Efavirenz Elvitegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI SingleTabletRegimens NRTI Tenofovir TAF Ritonavir Protease Emtricitabine Atazanavir Single Darunavir Abacavir Tablet Atripla 2006 Cobicistat Regimens Lamivudine Doravirine Raltegravir Efavirenz Elvitegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI SingleTabletRegimens SingleTabletRegimens NRTI Tenofovir TAF Ritonavir Protease NRTI Tenofovir TAF Ritonavir Protease Emtricitabine Emtricitabine Atazanavir Atazanavir Darunavir Darunavir Abacavir Abacavir Stribild Cobicistat Cobicistat Complera Lamivudine Lamivudine August, August,2012 2011 Doravirine Raltegravir Doravirine Raltegravir Efavirenz Elvitegravir Efavirenz Elvitegravir Rilpivirine Dolutegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI NNRTI Bictegravir INSTI SingleTabletRegimens SingleTabletRegimens NRTI Tenofovir TAF Ritonavir Protease NRTI Tenofovir TAF Ritonavir Protease Emtricitabine Emtricitabine Atazanavir Atazanavir Darunavir Darunavir Abacavir Abacavir Cobicistat Cobicistat Odefsey Lamivudine Lamivudine March,2016 Doravirine Raltegravir Doravirine Raltegravir Triumeq Efavirenz Elvitegravir Efavirenz August,2014 Elvitegravir Rilpivirine Dolutegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI NNRTI Bictegravir INSTI SingleTabletRegimens SingleTabletRegimens NRTI Tenofovir TAF Ritonavir Protease NRTI Tenofovir TAF Ritonavir Protease Emtricitabine Emtricitabine Atazanavir Atazanavir Darunavir Darunavir Abacavir Abacavir Genvoya Symtuza Cobicistat July,2018 Cobicistat Lamivudine Lamivudine November,2015 Doravirine Raltegravir Doravirine Raltegravir Efavirenz Elvitegravir Efavirenz Elvitegravir Rilpivirine Dolutegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI NNRTI Bictegravir INSTI SingleTabletRegimens SingleTabletRegimens NRTI Tenofovir TAF Ritonavir Protease NRTI Tenofovir TAF Ritonavir Protease Emtricitabine Emtricitabine Atazanavir Atazanavir Darunavir Darunavir Abacavir Abacavir Cobicistat Cobicistat Delstrigo Lamivudine Lamivudine August,2018 Doravirine Raltegravir Doravirine Raltegravir Biktarvy Efavirenz February,2018 Elvitegravir Efavirenz Elvitegravir Rilpivirine Dolutegravir Rilpivirine Dolutegravir NNRTI Bictegravir INSTI NNRTI Bictegravir INSTI U.S.DHHSGuidelineUpdate:October,2018 Case1 InitialRegimens InitialRegimens “forMostPeople” “inCertainClinicalSituations” •51yearoldmanregisteringforcare.VL=41,000,CD4+count=682. BIC/TAF/FTC EVG/cobi +(TDF/FTCorTAF/FTC) Creatinine=1.4,andeGFR =55 mL/min.LDL=68.HLAB57Ǧ01isnegative. *Ifreproductivepotential,consultguidance *Ifreproductivepotential,consultguidance Noothermedicalproblems.Whichregimen(s)wouldyouoffer? DTG/ABC/3TC RAL/ABC/3TC OnlyifHLB57Ǧ01negative OnlyifHLAB57negativeandVL<100,000 •A)TDF/FTC(Truvada)+DTG(Tivicay)Æ eGFRis<60:avoidTDF. *Ifreproductivepotential,consultguidance *Ifreproductivepotential,consultguidance •B)TAF/FTC(Descovy)+DTG(Tivicay)Æ Finechoice. DTG +(TDF/FTC orTAF/FTC) (DRV/RTVorDRV/cobi)+(TDF/FTCorTAF/FTC) •C)ABC/3TC/DTG(Triumeq)Æ Finechoice. RAL +(TDF/FTCorTAF/FTC) (DRV/cobi orDRV/RTV)+ABC/3TC –B57negative,thuseligible.NomajorCVconcerns.Triumeq foreGFR>50. OnlyifHLB57Ǧ01negative •D)TDF/FTC(Truvada)+RTV/DRVÆ eGFRis<60:wouldavoidTDF,and (ATV/cobi orATV/RTV)+(TDF/FTCorTAF/FTC) Organizationalcomments: especiallyincombinationwithRTV/PI,whichboostsTDF.Also,secondline. • BIC/TAF/FTCnewin2018... (ATV/cobi orATVRTV)+ABC/3TC •DORaddedtosecondlinein2018... OnlyifHLAB57negativeandVL<100,000 •E)EVG/cobi/TAF/FTC(Genvoya)Æ eligiblesinceGFRis>30,butfavor •DRVmovedoutoffirstlinelistin2017… unboosted INSTIinsteadofusingcobi.Also,secondline. • EVG/cobi/TAF/FTCandEVG/cobi/TDF/FTC DOR +(TDF/FTCorTAF/FTC) movedoutoffirstlinein2018… •F)RAL+TAF/FTC(Descovy)Æ Fine,butpreferpotency/geneticbarrierof •Guidelinesdon’treallyemphasizeTAFvs. EFV +(TDF/FTCorTAF/FTC) TDFmuch… DTGorBIC. RPV +(TDF/FTCorTAF/FTC) Adaptedfrom:USDHHSARTGuidelines–October28,2018Update OnlyifVL<100,000&CD4+>200 Case1 Case2 •51yearoldmanregisteringforcare.VL=41,000,CD4+count= •SamepatientasCase1,butlowereGFR: 682.Creatinine=1.4,andeGFR =55mL/min.LDL=68. •51yearoldmanregisteringforcare.VL=41,000,CD4+count=682. HLAB57Ǧ01isnegative.Noothermedicalproblems.Which Creatinine=1.6,andeGFR =31mL/min.LDL=68.HLAB57Ǧ01isnegative. Noothermedicalproblems.Whichregimenwouldyouoffer? regimen(s)wouldyouoffer? •A)TDF/FTC(Truvada)+DTG •A)TAF/FTC/BIC(Biktarvy) •B)TAF/FTC(Descovy)+DTG •B)TAF/FTC(Descovy)+DTG(Tivicay) •C)TAF/FTC/BIC(Biktarvy) •C)ABC/3TC/DTG(Triumeq) • ABC/3TC/DTG(Triumeq) •D)TDF/FTC(Truvada)+RTV/DRV •D)TDF/FTC+RTV/DRV •E)EVG/cobi/TAF/FTC(Genvoya) •E)EVG/cobi/TAF/FTC(Genvoya) •F)RAL+TAF/FTC(Descovy) •F)TAF/FTC(Descovy)+RAL1200QD Case2 Case3 •A)TDF/FTC(Truvada)+DTG •48y.o.man,newly diagnosed,VL •51yearoldmanregisteringforcare.VL=41,000,CD4+count=682. –eGFR>60isok,butwith1+proteinuria,favorTAF 105,000,CD4+= Creatinine=1.6,andeGFR =31mL/min.LDL=68.HLAB57Ǧ01isnegative. overTDF Noothermedicalproblems.Whichregimenwouldyouoffer? 487.Has •B)TAF/FTC(Descovy)+DTG hyperlipidemia (LDL •A)TDF/FTC(Truvada)+DTGÆ eGFRis<60:avoidTDF –OKchoice,eGFR>30,butalreadyhasproteinuria… =140,Total •C)TAF/FTC/BIC(Biktarvy) cholesterol=221), •B)TAF/FTC(Descovy)+DTGÆ eGFRis>30:finechoice;monitor. smokes 10 –OKchoice,eGFR>30,butalreadyhasproteinuria… •C)TAF/FTC/BIC(Biktarvy)Æ eGFRis>30:finechoice;monitor. cigarettes/day, •D)ABC/3TC/DTG(Triumeq) •D)ABC/3TC/DTG(Triumeq) HBA1c=7.1%, –OKchoice,eGFR>50;butwithCVriskfactors BUN/creatinine –B57negative:eligible.SomeCVconcernswithrenaldisease. (lipids/smoking/DM),balanceCVriskwithABCvs. 14/1.2,eGFR=73 –ButTriumeq isonlyforeGFR>50. usingTAFinpatientwithproteinuria mL/min,UA:1+ •D)TDF/FTC+RTV/DRVÆ eGFRis<60:avoidTDF,esp.withRTV/PI. •E)TAF/FTC+RTV/DRV protein.WhichART isoptimal? •E)EVG/cobi/TAF/FTC(Genvoya)Æ SinceeGFR<70,favorunboosted INSTI –Withcardiacandrenalriskfactors,avoidPIif •F)TAF/FTC(Descovy)+RAL1200QDÆ FinechoiceateGFR>30,butlower possible.Secondline. barriertoresistance,and3pillswheresingletabletispossible •F)TDF/FTC/DOR(Delstrigo) –Withproteinuria,avoidTDF.Secondline. Case3 Case4 •48y.o.man,newlydiagnosedlastmonth,VL105,000,CD4+ •34y.o.woman,VL23,000,CD4+610.HaschronicHBV: count=487.Hashistoryofhyperlipidemia(LDL=140,Total HBsAg+HBsAb+HBcAb+HBVDNA=6MIU/mL. HLAB57Ǧ01 cholesterol=221),smokes 10cigarettes/day,andhasHBA1c negative.eGFR=90.Whichregimen(s)wouldyouoffer? =7.1%.BUN/creatinine 14/1.2,eGFR=73mL/min,UA:1+ protein.WhichARTisoptimal? •A)TAF/FTC(Descovy)+DTG •A)TAF/FTC(Descovy)+DTG •B)TDF/FTC(Truvada)+DTG •B)TDF/FTC(Truvada)+DTG •C)TAF/FTC/BIC(Biktarvy) •C)TAF/FTC/BIC(Biktarvy) •D)ABC/3TC/DTG(Triumeq) •D)ABC/3TC/DTG(Triumeq) •E)TDF/FTC(Truvada)+RTV/DRV •E)TAF/FTC(Descovy)+RTV/DRV •F)ABC/3TC(Epzicom)+RAL •F)TDF/FTC/DOR(Delstrigo) Case4 Case5 •34y.o.woman,HIVVL123,000,CD4+610.HaschronicHBV: •57y.o.woman,VL=14K,CD4=390.DM2:A1c=8.0%,takesmetforminat HBsAg+HBsAb+HBcAb+HBVDNA+.HLAB57Ǧ01negative. maximum850mgTIDdose+glipizide 5mgBID,eGFR=90,UAwithno protein.HLAB57negative.WhichARTregimendoyoufavor? eGFR=90.Whichregimen(s)wouldyouoffer? • Potentiallyok;potentiallynot •DTGboostsmetforminÆ wouldneedclosemonitoringas •A)TAF/FTC(Descovy)+DTG Æ finechoice A)TDF/FTC(Truvada)+DTG alreadyonmaxdose(butmightbeok) nd Æ finechoice •Ifneedtoreducemetformin,mighthavetoadd2 med,or •B)TDF/FTC(Truvada)+DTG DM2controlmaygetworse •C)TAF/FTC/BIC(Biktarvy) Æ finechoice B)TAF/FTC(Descovy)+DTG •SameaschoiceA •D)ABC/3TC/DTG(Triumeq)Æ 3TCalone:wouldaddentecavir C)TAF/FTC/BIC(Biktarvy) •SameaschoiceA •E)TDF/FTC(Truvada)+RTV/DRVÆ OK,butpreferintegrase>PI “DDI”=drugǦ D)ABC/3TC/DTG(Triumeq) •SameaschoiceA druginteraction* •F)ABC/3TC(Epzicom)+RALÆ Comboissecondline,notforHIV •eGFR>70,noDDI*Æ finechoice, E)TDF/FTC/cobi/EVG(Stribild) VL>100K(alwayscheck),wouldneedtoaddentecavirwith3TC,and •butprefer toavoidcobicistat ifRALpossible wouldpreferintegraseoverPI •eGFR>30,noDDI*Æ finechoice F)TAF/FTC(Truvada)+RAL • BalanceyourviewofRALvs.DTG/BIC againstDMcontrol Case5 Whatabout”2ǦDrugTherapy”forInitiation? •57y.o.woman,VL=14K,CD4=390.DM2:A1c=8.0%, • Dolutegravir/rilpivirine (Juluca) takesmetformin atmaximum875mgTIDdose+ •FDAapproved11/21/17formaintenanceforHIVtherapy(i.e., glipizide 5mgBID,eGFR=90,UAwithnoprotein. switchoftherapyinavirallysuppressedpatient) • SWORDǦ1&SWORDǦ2PhaseIIIswitchstudies:DTG/RPV95% HLAB57negative.WhichARTregimendoyoufavor? VS@W48vs.Control:95%VS,differenceǦ0.2%(Ǧ3.0—+2.5%) •DataonARTǦnaïve patientsnotyetavailable… •A)TAF/FTC(Descovy)+DTG Lilbre JM.etal,Lancet,March2018 •B)TDF/FTC(Truvada)+DTG • Dolutegravir/3TC •C)TAF/FTC/BIC(Biktarvy) • GEMINIǦ1&GEMINIǦ2: DTG/3TCvs.DTG/TDF/FTCinARTǦnaïve patients •D)ABC/3TC/DTG(Triumeq) • Week48viralsuppression91%(DTG/3TC)vs93%(DTG/TDF/FTC) •E)TDF/FTC/cobi/EVG(Stribild) CahnP.etal,Lancet,November2018 •F)TAF/FTC(Truvada)+RAL Summary/Principles References(2) • ChoosingtheNRTI backbone: •WohlDetal.BriefReport:ARandomized,DoubleǦBlindComparisonofTenofovirAlafenamideVersusTenofovirDisoproxil –ConsiderTDFvs.TAF Fumarate,EachCoformulated WithElvitegravir,Cobicistat,andEmtricitabineforInitialHIVǦ1Treatment:Week96Results.JAIDS. • AssesseGFR,proteinuria,osteoporosis,importanceofpillsize 2016May1;72(1):58Ǧ64.doi:10.1097/QAI.0000000000000940.PMID:26829661 –ConsiderABCvs.TDF/TAF • Arribas JRetal.BriefReport:Randomized,DoubleǦBlindComparisonofTenofovirAlafenamide(TAF)vsTenofovirDisoproxil • NeedHLAB57Ǧ01test.Assessquestion/opinionofcardiacriskissues Fumarate(TDF),EachCoformulated WithElvitegravir,Cobicistat,andEmtricitabine(E/C/F)forInitialHIVǦ1Treatment:Week144 –ConsultwithexpertswhenallNRTI’sseemproblematic Results.JAIDS.2017Jun1;75(2):211Ǧ218.doi:10.1097/QAI.0000000000001350.PMID:28282300 •CurtisLetal.Dolutegravir:clinicalandlaboratorysafetyinintegraseinhibitorǦnaivepatients.HIVClin Trials.2014SepǦ •GoalistouseINSTIinmostpatientsunlessotherissuesprevail Oct;15(5):199Ǧ208.doi:10.1310/hct1505Ǧ199.PMID:25350958 –Considerpriorhistory,drugintolerance,sideeffect,desireforsingleǦ •deBoerMG,etal.IntoleranceofdolutegravirǦcontainingcombinationantiretroviraltherapyregimensinrealǦlifeclinicalpractice. tabletregimen,druginteractions AIDS.2016Nov28;30(18):2831Ǧ2834.PMID:27824625 –ConsiderDTG,BICformostpatientsifpossible • Ripamonti Detal.Drugreactionwitheosinophiliaandsystemicsymptomsassociatedwithraltegravir use:casereportandreview oftheliterature.AIDS.2014Apr24;28(7):1077Ǧ9.doi:10.1097/QAD.0000000000000204.PMID:24685746 • AssessPIandNNRTIpossibilitiesifneeded: –Considerdosing(QDvs.BID),desireforsingletabletregimen,psychiatric •SaxPEetal.Coformulated bictegravir,emtricitabine,andtenofovir alafenamide versusdolutegravir withemtricitabine and tenofovir alafenamide,forinitialtreatmentofHIVǦ1infection(GSǦUSǦ380Ǧ1490):arandomised,doubleǦblind,multicentre,phase history,lipidprofile,GIissues,renalstatus,likelihoodofstrong 3,nonǦinferioritytrial.Lancet.2017.Nov4;390(10107):2073Ǧ2082.doi:10.1016/S0140Ǧ6736(17)32340Ǧ1.PMID:28867499 adherence/geneticbarrier – AssessbaselineVLandCD4count •FocusonDHHSfirstǦlinerecommendedregimens References References(3) •PanelonAntiretroviralGuidelinesforAdultsandAdolescents.GuidelinesfortheUseofAntiretroviralAgentsinAdultsand AdolescentsLivingwithHIV.DepartmentofHealthandHumanServices.Version:October17,2017.Availableat: • GallantJetal.Bictegravir,emtricitabine,andtenofoviralafenamideversusdolutegravir,abacavir,andlamivudineforinitial http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.Accessed11/1/17. treatmentofHIVǦ1infection(GSǦUSǦ380Ǧ1489):adoubleǦblind,multicentre,phase3,randomised controllednonǦinferioritytrial. Lancet.2017Nov4;390(10107):2063Ǧ2072.doi:10.1016/S0140Ǧ6736(17)32299Ǧ7.PMID:28867497 •LapriseCetal.Associationbetweentenofovir exposureandreducedkidneyfunctioninacohortofHIVǦpositivepatients:results from10yearsoffollowǦup.2013.Clin InfectDis.Feb;56(4):567Ǧ75.doi:10.1093/cid/cis937.PMID:23143096 •EronJJetal.AweekǦ48randomizedphaseǦ3trialofdarunavir/cobicistat/emtricitabine/tenofoviralafenamideintreatmentǦnaive HIVǦ1patients.AIDS. 2018Jul17;32(11):1431Ǧ1442.doi:10.1097/QAD.0000000000001817.PMID:29683855 •NishijimaTetal.LongǦtermexposuretotenofovir continuouslydecreaserenalfunctioninHIVǦ1Ǧinfectedpatientswithlowbody weight:resultsfrom10yearsoffollowǦup.AIDS.2014.Aug 24;28(13):1903Ǧ10.doi:10.1097/QAD.0000000000000347.PMID: •OrkinCetal.Efficacyandsafetyofswitchingfromboostedproteaseinhibitorsplusemtricitabineandtenofovirdisoproxil 25259702 fumarateregimenstosingleǦtabletdarunavir,cobicistat,emtricitabine,andtenofoviralafenamideat48weeksinadultswith virologically suppressedHIVǦ1(EMERALD):aphase3,randomised,nonǦinferioritytrial.LancetHIV.2017Oct 5.pii:S2352Ǧ 3018(17)30179Ǧ0.doi:10.1016/S2352Ǧ3018(17)30179Ǧ0.PMID:28993180 • CooperRDetal.SystematicreviewandmetaǦanalysis:renalsafetyoftenofovirdisoproxilfumarateinHIVǦinfectedpatients.Clin InfectDis.2010.Sep1;51(5):496Ǧ505.doi:10.1086/655681.PMID:20673002 • Lilbre JMetal.Efficacy,safety,andtolerabilityofdolutegravirǦrilpivirine forthemaintenanceofvirological suppressioninadults withHIVǦ1:phase3,randomised,nonǦinferioritySWORDǦ1andSWORDǦ2studies.Lancet. 2018Mar3;391(10123):839Ǧ849.doi: •McComseyGAetal.BonemineraldensityandfracturesinantiretroviralǦnaivepersonsrandomizedtoreceiveabacavirǦlamivudine 10.1016/S0140Ǧ6736(17)33095Ǧ7.PMID:29310899 ortenofovirdisoproxilfumarateǦemtricitabinealongwithefavirenzoratazanavirǦritonavir:AidsClinicalTrialsGroupA5224s,a substudyofACTGA5202.JInfectDis.2011.Jun15;203(12):1791Ǧ801.doi:10.1093/infdis/jir188.PMID:21606537 •Cahn,P.etal.Dolutegravirpluslamivudineversusdolutegravirplustenofovirdisoproxilfumarateandemtricitabinein antiretroviralǦnaiveadultswithHIVǦ1infection(GEMINIǦ1andGEMINIǦ2):week48resultsfromtwomulticentre,doubleǦblind, •SaxPEetal.Tenofoviralafenamideversustenofovirdisoproxilfumarate,coformulatedwithelvitegravir,cobicistat,and randomised,nonǦinferiority,phase3trials.Lancet.2018Nov9.pii:S0140Ǧ6736(18)32462Ǧ0.doi:10.1016/S0140Ǧ6736(18)32462Ǧ0. emtricitabine,forinitialtreatmentofHIVǦ1infection:tworandomised,doubleǦblind,phase3,nonǦinferioritytrials.Lancet.2015. PMID:30420123. Jun27;385(9987):2606Ǧ15.doi:10.1016/S0140Ǧ6736(15)60616ǦX.PMID:25890673 ThankYou! • Happytotake anyquestions! •Forquestions afterthe conference: – [email protected] – pleaseemailme anytime ϭϭͬϮϵͬϮϬϭϴ /ŚĂǀĞŶŽĚŝƐĐůŽƐƵƌĞƐ͘ /ŶƚĞƌĞƐƚŝŶŐĂƐĞƐŝŶ,/s DĞĚŝĐŝŶĞ ůŝnjĂďĞƚŚ/ŵďĞƌƚ͕DDW, ƐƐŝƐƚĂŶƚWƌŽĨĞƐƐŽƌ ŝǀŝƐŝŽŶŽĨ,/s͕/͕ĂŶĚ'ůŽďĂůDĞĚŝĐŝŶĞ ƵĐŬĞƌďĞƌŐ^ĂŶ&ƌĂŶĐŝƐĐŽ'ĞŶĞƌĂů h^& ĂƐĞϭ ϰϲŚŽŵĞůĞƐƐŶĞƐƐŵĂŶǁŚŽŚĂƐƐĞdžǁŝƚŚŵĞŶĂŶĚǁŽŵĞŶĂŶĚƵƐĞƐ/s KŶĞdžĂŵ͕sͬ^ϭϮϱͬϳϲWϭϮϳdϯϳ͘ϳZZϭϮKϮƐĂƚϵϳйŽŶZ͘ džĂŵŶŽƚĂďůĞ ŵĞƚŚ͕ǁŚŽǁĂƐƌĞĐĞŶƚůLJĚŝĂŐŶŽƐĞĚĂƚĂŶŽƵƚƐŝĚĞŚŽƐƉŝƚĂůǁŝƚŚ,/s ĨŽƌƚŚƌƵƐŚĂŶĚĞƌLJƚŚĞŵĂƚŽƵƐĞĚĞŵĂƚŽƵƐĂƌĞĂŽǀĞƌůLJŝŶŐZƐƚĞƌŶŽĐůĂǀŝĐƵůĂƌ ũŽŝŶƚǁŝƚŚƚĞŶĚĞƌŶĞƐƐƚŽƉĂůƉĂƚŝŽŶ͘ ĂĨƚĞƌƉƌĞƐĞŶƚŝŶŐǁŝƚŚŵŽŶƚŚƐŽĨĨĞǀĞƌͬƐǁĞĂƚƐͬǁĞŝŐŚƚůŽƐƐ͘,ĞǁĂƐŶŽƚ ƐƚĂƌƚĞĚŽŶZs^ĂŶĚŶŽǁƉƌĞƐĞŶƚƐƚŽƵƌŐĞŶƚĐĂƌĞǁŝƚŚĐŽŶƚŝŶƵĞĚ ͗ϰ͘ϰфϴ͘ϮхϯϮϵ ĐŽŶƐƚŝƚƵƚŝŽŶĂůƐLJŵƉƚŽŵƐĂƐǁĞůůĂƐŶĞĐŬĂŶĚĐŚĞƐƚƉĂŝŶ͘ DW͗tE> >,͗ϮϬϱ ZWϲϲ͘ϱ ^Z͗ϭϯϮ ϰ͗ϴϭ s>͗ϴϰϴ< ϭ ϭϭͬϮϵͬϮϬϭϴ ĚĚŝƚŝŽŶĂůǁŽƌŬͲƵƉ dŶĞĐŬƐŚŽǁĞĚZ ,ŝƐďůŽŽĚĐdžĨƌŽŵŽƵƚƐŝĚĞŚŽƐƉŝƚĂůŐƌĞǁ^ƚĂƉŚƐĐŚůĞŝĨĞƌŝ ŝŶϮͬϮ͘ ƐƚĞƌŶŽĐůĂǀŝĐƵůĂƌŽƐƚĞŽůLJƐŝƐ ĂŶĚ ZĞƉĞĂƚďůŽŽĚĐdžǁĞƌĞE'd͘ 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ĐͬŽĨĞǀĞƌƐ͕ŵĂůĂŝƐĞĂŶĚŶŽŶͲƉƌŽĚƵĐƚŝǀĞĐŽƵŐŚdžǁĞĞŬƐĂŶĚϭͲϮůŽŽƐĞ ŝŶŐƵŝŶĂů>ǁŚŝĐŚƐŚŽǁƐƌĞĂĐƚŝǀĞĐŚĂŶŐĞƐ͘ ƐƚŽŽůƐƉĞƌĚĂLJ͘ sͬ^dϯϴ͘ϳ͕WϭϮϳ͕WϭϭϱͬϳϬ͕KϮƐĂƚϵϴйZ͘ ,ĞŝƐĂĚŵŝƚƚĞĚƚŽŵĞĚŝĐŝŶĞĂŶĚďůŽŽĚĐdžĨƌŽŵW/ƌĞƚƵƌŶD^^ĂŶĚ ƐƚŽŽůĐdžƌĞƚƵƌŶƐнĨŽƌĚŝĨĨ͘ ĞƐƉŝƚĞWKǀĂŶĐŽŵLJĐŝŶĂŶĚ/sǀĂŶĐŽŵLJĐŝŶ͕ŚĞƌĞŵĂŝŶƐƉĞƌƐŝƐƚĞŶƚůLJ ĨĞďƌŝůĞ͘ ϳ ϭϭͬϮϵͬϮϬϭϴ ,ĞƵŶĚĞƌŐŽĞƐ&EŽĨ>ŝŶŐƵŝŶĂů>E͙ &EƌĞǀĞĂůƐ͙ ,,sͲϴнŵƵůƚŝĐĞŶƚƌŝĐ ĂƐƚĞůŵĂŶ͛Ɛ ĚŝƐĞĂƐĞ &ŝŶĂůĚŝĂŐŶŽƐŝƐ DƵůƚŝĐĞŶƚƌŝĐ ĂƐƚůĞŵĂŶ͛Ɛ ĚŝƐĞĂƐĞ ϴ CASE 1: COPING WITH PILL FATIGUE PREP 28 year-old HIV-negative MSM CC: Rectal Mass and Diarrhea x 2 weeks CASES PMH: No chronic medical issues - Diagnosed with secondary syphilis 9 months ago (RPR 1:512-> 1:4) - Rectal gonorrhea 3 months ago - Previously taking TDF/FTC for HIV prevention but stopped due to pill BREAKOUT fatigue 3 months ago MATT SPINELLI, MD SH: 3 Partners (receptive anal sex, inconsistent condom use) last month RESEARCH FELLOW, INFECTIOUS DISEASES - Drugs: Meth and GHB occasional around the time of sex DIVISION OF HIV, ID, AND GLOBAL MEDICINE - Stably housed, lives alone PE/LABS Afebrile, 128/78 HR 88 Tired-appearing OP clear/No LAN Heart: No MRG/Lungs: CTAB/Abdomen: NTND No rash Rectal: 1-2cm mass palpated at rectal verge, tender to palpation 6.1 > 12.2 < 250 Creatinine 1.1 HIV Ag/Ab NR; RNA UD RPR 1:512->1:4 HCV NR HBV SAb+ Sag- Core- Dhawan et al. Ind. J. Path & Micro 2017 LYMPHOGRANULOMA WILL PREP WORK WITH SO MANY VENEREUM PRESENTATION STIS? AND MANAGEMENT RECCS. Chlamydia serotypes L1-3 • Strong evidence that PrEP is effective in the setting of STIs Primary stage (3-30 days) denoted by a • Syphilis incidence 7.2/100 PY in iPrEx-OLE, did not differ small, painless ulcer 3-30 days post- between among those who did/did not elect to take PrEP; exposure no difference in efficacy (Grant et al. Lancet ID 2014) Secondary stage (10-30 days after • Relationship between PrEP and risk behavior is primary): tender inguinal and/or inconclusiveÆ important to meet people where they are at femoral lymphadenopathy (genital exposure), or hemorrhagic proctitis or proctocolitis (anal exposure) • A portion of increased STIs seen in PrEP users is a result of screening detecting asymptomatic infections (Traeger et If confirmatory testing unavailable or al. AIDS 2018 #THAC0502) high turnaround time, consider doxycycline x 21 days for rectal CT+ and proctitis SFDPH STD Control Health Alert 2004 HIGH INCIDENCE OF HCV WE NEED TO SCREEN OR STIS REINFECTION IN PREP USERS MAY INCREASE Model of national GC/CT incidence per Male gonococcus cases in SF1 proportion screened over 6 month intervals2 • AMPrEP: PrEP Demo with 376 MSM and TGW in Amsterdam • Tested every 6 months for HCV • Incidence of primary infection: 1.0/100 py (95%CI 0.5-2.2) (n=6) • Incidence of re-infection: cases of Number 25.5/100 py (95%CI 11.5-56.8) (n=6) Hoornenborg et al. 1. SF HIV Epi. 2016 AIDS 2018 TUPDX0104 2. Jenness et al. CROI 2017 #1034 RETENTION IN CARE: “SOON TO BE MOST CRUCIAL ISSUE IS HE A PREP CANDIDATE? IN PREP IMPLEMENTATION”1 How do we address his pill 38% on PrEP at fatigue? review end ֳ Median ֳ time on PrEP: 8 months 1. Golub. Lancet HIV 2018 2. Spinelli et al. HIVR4P # OA 19.02 TOP 5 REASONS WHY COPING WITH PILL PEOPLE STOP PREP FATIGUE 1. Self-perceived low risk Could on-demand PrEP (2-1-1) help with pill fatigue? 2. Cost or changes in coverage • Montreal cohort offered 3. Medication side effects (actual or anticipated) intermittent vs. daily PrEP • Consistent use 4. Pill fatigue • 34% for daily • 43% for 5. Difficulty adhering to provider/lab appointments intermittent • P=0.02 Greenwald et al, CROI 2018, #1038 Buchbinder HIVR4P 2018 #SA16.2 Buchbinder HIVR4P 2018 #SA16.2 NOEndorsed HIV INFECTIONS by IAS-USA IN Guidelines: EITHER REAL WORD ON-DEMAND PREP GROUPSaag et al. JAMA 2018 SCENARIOS Follow-Up HIV Incidence Treatment Pts-years per 100 Pts-years (95% CI) TDF/FTC (Daily) 443 0 (0-0.8) TDF/FTC (On Demand) 506 0 (0-0.7) Mean follow-up: 7 months (SD: 4) 85 HIV-infections averted* * assuming an incidence of 9.17/100 PY as observed in the ANRS Ipergay study in Paris Molina et al. AIDS 2018 http://i-base.info/guides/prep/real-life- WEAE0406LB examples-for-on-demand-dosing WHAT WOULD YOU DO CASE 2: “THREE-DRUG” PREP? NEXT? 39 y/o M with meth use disorder (injection) who has sex w/ M A) Repeat Ag/Ab, start PrEP if negative • Interested in starting PrEP, uses shared injection B) Obtain HIV viral load, start PrEP if negative equipment, 2 receptive CAI partners last month C) Start PrEP today • Lives in a shelter with difficulty remembering to take meds D) Start PrEP today, order HIV viral load just in case • Endorses sore throat and chills, last sexual contact two E) Start ART today, order HIV viral load weeks ago • Vitals/Exam unremarkable, OP clear, no rash • Labs: HIV Ag/ab negative 5 days ago, Cr 0.9, HBV negative, HCV Ab +, HCV VL pending, STI testing pending PHARYNGEAL GC+ FOLLOW-UP VISIT Viral load returned <40 • Reported one month later to pharmacist -> he had been assaulted 4 days prior Received ceftriaxone and azithromycin Started PrEP within three days • Thinks he was drugged at a Folsom Street party, woke up with Visited Ward 86 pharmacy once a week to pick up HCV meds needles in his arms and pick up PrEP (concerns about theft at shelter) Vaccinated for HBV • Friend told him that he had sex with a person living with HIV • Pharmacist reported he had not picked up PrEP for >1 week WHAT WOULD YOU DO NEXT? FOLLOW-UP A) Reinitiate PrEP, he should be protected • Seen in urgent care, not started on PEP or restarted on PrEP due to being “out of the PEP window” B) Hold PrEP, outside of the window for PEP, re-test within 2-4 weeks and reinitiate PrEP • Lost to follow-up C) Initiate DTG + TDF/FTC, plan to transition back to PrEP if • Returned two weeks later with subjective fever and sore- HIV testing negative throat D) Initiate DTG + DRV/C + TDF/FTC, plan to transition back to PrEP if HIV testing negative NOT AGAIN! WHAT WOULD YOU DO? TEACHING POINTS A. Hold meds, if viral load detectable, initiate DTG+ TDF/FTC • STIs are on the rise, seeing more unusual presentations of for likely acute infection syphilis and remember LGV B. Initiate DTG + TDF/FTC to treat likely ARS; continue • PrEP works in the settings of STIs; don’t forget to screen indefinitely as testing could be unreliable C. Initiate DTG + TDF/FTC, stop dolutegravir if viral load • Patients face barriers to adherence and retention in care; undetectable and continue TDF/FTC for PrEP check in with your patients • Intermittent PrEP is a good option for patients who can’t • Started on DTG + TDF/FTC take daily PrEP, particularly if they have infrequent sex • Viral load returned UD • Be vigilant for acute HIV in your PrEP patients, consider three or four drug therapy when in doubt, particularly if • Dolutegravir stopped and continued PrEP once result they remain at consistent risk of HIV returned Disclosures • InvestigatorͲinitiatedfundingto: – EnrollearlyHIVͲinfectedindividuals MedicalManagementof – ProvideimmediateART(Descovy andTivicay) – TostudyhostresponsesduringearlyHIVinfectionthat HIV/AIDS mightleadtonovelHIVcurestrategies PrEPClinicalCases Company Relationship Viiv HealthcareInvestigatorͲinitiatedresearchfunding SulggiLee,M.D.,Ph.D. GileadSciencesInvestigatorͲinitiatedresearchfunding AssistantProfessorofMedicineUCSF Thefundershavenoroleinstudydesign,datacollection, DivisionofHIV,InfectiousDiseases,andGlobalMedicine analysis,orpublicationofthework. December7,2018 Case1 HPI • Consultfromaninternistataprivatemedical • PrEPx1yearwith“100%compliance” clinic • Currentpartnerx2yearsalsoonPrEPbut “poorcompliance” • 24yo gayͲidentifiedmalecompliantonoral • “Open”relationship(~1newpartner/month) dailyPrEPwith“discordantHIVtestresults” • LastHIVneg test3mo ago • Lastsex3weeksago ROS PMH • Nofevers,sweats • Anxiety • Anorexia“duetostress”x6monthsafterrecent promotionatwork • Bipolardisorderwithdissociativefugue • Wt loss“80lbs overthelastsixmonths” • Hx ofpriorinvoluntarypsychadmissionas • Fatigue“severe” teen • Nausea/vomiting“everymorningsinceIwasateen” • Asthma“seasonal” • Insomnia • Muscleaches“I’malwayssore” • Polysubstance use(cocaine,tobacco, • Nosorethroat,lymphadenopathy,rash,genitalororal marijuana,priorETOH) lesions,abdominalpain,CP,SOB,cough,neurologic deficits,urinaryorbowelhabitchanges Meds SocialHx • Truvada qd • BornandraisedinSacramentoandlivinginSF • Gabapentin300mg forpast5years.Highschooldegree. • Lorazepam prn • Priorsexworkerx6yearsuntil2yearsago(“I neverhadanSTDtheentiretime”). • NKDA Currentpartnerx2yearsinopenrelationship. • Reportsthathe“loveshavingsex”and“rarely usescondoms.” SocialHx FamilyHx • Currentlyworkinginrealestatemanagement • Nocontactwithfamilysincehewasage16. • Norecenttravel Hasonesisterwhowouldbeage28now. • Nopets Watchedhisgrandfather“dieofAIDS”when thepatientwas3yearsold. • Tobacco:1ppdx10years • ETOH:prior“heavy”butnow“occasional” • Drugs:cocainedependence–noneinprior8 monthsduetopartner’srequest.Marijuana use“frequently.”NoIVDU PhysicalExam Initial Clinical Labs PMD Office 16.8 RPR NR • NAD,anxiousͲappearing,tearful 4.7 193 Gonorrhea neg • Nothrush,noLAN,OPclear 48.5 Chlamydia neg nl diff • RRR,nom/r/g Hep A immune Hep B immune • CTAB 143 101 10 Hep C neg • SoftNTND.NoHSM.Norebound. 88 • Testicles,peniscircumcised,wnl. Nolesions. 4.6 22 0.91 • Noedema 1.1 Albumin 4.8 HIV 1/2 Ag/Ab pos • Nofocalneuro deficits 21 24 Total protein 7.1 HIV qualitative RNA neg 59 HowWouldYouInterpretTheseResults? WhatWouldYouDoNext? A. DefinitediagnosisofHIV A. RepeatAg/Ab test B. PossiblediagnosisofHIV B. Performrepeat C. Hehasafalsepositive confirmatoryantibodytest result C. Testhispartner D. Cannotbedetermined D. Repeatthequantitative withthesedataalone HIVRNA E. BandD E. Alloftheabove F. Noneoftheabove Study Enrollment Visit Repeat Labs from PMD Office (3 Weeks from Initial Clinical Visit) 16.8 RPR NR • Initialclinicalvisit: 4.7 193 Gonorrhea neg Chlamydia neg – HIV1/2Ag/Ab + 48.5 nl diff – Aptima qualitativeRNAͲ Hep A immune Hep B immune 141 103 15 Hep C neg • 1weeklater: 69 3.7 29 1.03 – HIV1/2Ag/Ab+ – Aptima qualitativeRNA+ HIV 1/2 Ag/Ab pos – VL<20copies/mL 2.5 Albumin 4.7 HIV qualitative RNA neg 29 30 Total protein 7.2 64 FurtherHPI CanPrEPbe“Overwhelmed?” • Perdiscussionwithpatient’sprimarycare • UnpublisheddatamodelingfromBobGrant’s provider SeroPrEP study – Patienthasepisodesofdissociativefugueduring – Suggeststhat>90sexactspermonthmightbea whichhehashighfrequencyunprotectedsex “threshold”thatcouldsurpassdailyoralPrEP oftenatbathhouses – Inthepasthashad>15partnersinasingle sessionwith>40partnersinaweek • Patientreportedlast“sexbinge”was~45 partnersinthe2weeksprecedinghisinitial indeterminateHIVtesting IncidenceAssayPerformanceinEarlyHIVInfection LaboratoryMarkerswithAcuteHIV ButwhatdoesPrEPdototheexpressionofthesemarkers?? ButwhatdoesPrEPdotothetimingofpositivityand interpretationofthesetests?? NationalHIVCurriculumathttps://www.hiv.uw.edu/go/screeningͲdiagnosis/diagnosticͲtesting/ NationalHIVCurriculumathttps://www.hiv.uw.edu/go/screeningͲdiagnosis/diagnosticͲtesting/ EffectsofPrEPonNATandAntibodies PrEPInterferencewithIncidenceTesting AcuteHIVInfection • Reducesanddelays • Suppressedviralreplication RNA/p24Ag RNAandp24 IgMantibodies – CanbebelowLODof – Falseneg evenwiththemostsensitiveNATassays IgGantibodies NAT • Reducesanddelays IgMandIgG responses • Interferencewithserologicalresponseinpatient – Cangetfalseneg on “4th Gen”EIAs – Falseneg antibodyresults,delayedresponses, AcuteHIVInfectiononPrEP • Cangetseroreversion seroreversions withEIAandWB • Bandsonwestern (HareCID 2006;KillianAIDSResHumRetr 2006;StephensonOFID 2016) RNA/p24Ag Antiretroviraltherapy blot/antiͲHIV antibodytestsmaybe delayedandatypical • UnusualpatternsofserologyandNATtesting IgMantibodies IgGantibodies – NAT‘positive’signalwithoutseroconversion – Negative,indeterminatewesternblots/EIAs KeatingCID2016 Infectious AntibodyResponseis“Aborted”withEarlyART Units andResumeswithTreatmentInterruption PlasmaRNA HIVMeasurements Ͳ CellͲassociatedDNA Ͳ CellͲassociatedRNA Ͳ PlasmaHIVRNA Ͳ Infectiousunits N=7withUDVL@4WKATI N=10with+VL@4WKATI Stephenson OFID 2016 PasternakRetrovirology 2013 CaseTimeline ClinicalPlasmaHIVRNAAssays CLINICAL VISIT: STD TESTING - HIV 1/2 Ag/Ab POS - Geenius differentiation neg - Aptima “qualitative” RNA neg • Aptima TMA–falsepositive=0.5% CLINICAL VISIT 2: STD TESTING - HIV 1/2 Ag/Ab POS - Geenius differentiation neg – - Aptima “qualitative” RNA POS (1outof200)werefalselypositivewhentruly - HIV RNA <20 negative(comparedtoacellͲassociatedDNA). PrEPx1year RESEARCH STUDY BASELINE Ͳ HIV1/2Ag/Ab neg Ͳ PlasmaHIVRNA<40 Ͳ Detuned0.07(neg oracute) – Onlya0.5%chancethatthisisafalsepositive. Exposure RESEARCH ASSAYS Ͳ UltrasensitivePlasmaHIVRNAneg Ͳ CellͲassociatedDNAneg Ͳ CellͲassociatedRNAPOS 2/2reps=117copes/106 PBMCs • RocheTaqman2hasapproximatelysensitivity Repeattestingneg downto~5copies -12 mo - 3 mo -1 mo -2 wk 0 1 wk 1 mo 2 mo Time Fiscus JCM2013;PasJCM2013 EffectsofPrEPonNATandAntibodies ImplicationsforHIVCure AcuteHIVInfection We Have Yet to Uncover Where Latent HIV Virus Hides • Reducesanddelays RNA/p24Ag RNAandp24 IgMantibodies – CanbebelowLODof IgGantibodies NAT • Reducesanddelays IgMandIgG responses – Cangetfalseneg on ART DOES ART/the immune “4th Gen”EIAs NOT kill system DOES AcuteHIVInfectiononPrEP • Cangetseroreversion these cells! NOT penetrate • Bandsonwestern these sites well RNA/p24Ag Antiretroviraltherapy blot/antiͲHIV antibodytestsmaybe delayedandatypical IgMantibodies IgGantibodies KeatingCID2016 Stevenson Scientific American 2008 ImplicationsforHIVCure MississippiBaby– Virus Persists in Dormant T Cells UndetectableHIVRNAOffART Baby started on ART immediately after birth Lost to follow up at 18 months and VL remained suppressed But then VL rebound 27 months later . . . ART DO NOT kill these cells! Stevenson Scientific American 2008 Persaud NEJM 2013 PrEPDemoParticipantStartedART DecidedtoUndergoAnalyticTreatment ~12DaysafterHIVInfection... Interruption– ReboundedatDay230 Patient started on ART ~12 days from infection Day 230 CD4+Count 220 copies/mL PlasmaHIVRNA Henrich Deeks PLoS Med 2017 Henrich Deeks Plos Med 2017 ExampleofASterilizingCure? CaseSummary • LongͲtermHIV+ART+ • Noabilitytodefinitivelyconfirmifpatientwas • Developedleukemia2007 indeedHIV+ • Afterchemotherapyfailed – PatientelectedtocontinuewithfullART Æ bonemarrowtransplant fromdonorwith2copiesof – NoissueswithstigmaorcarryingdiagnosisofHIV protectiveCCR5mutation – PMDinagreementgivenhighrisksexactivity (CCR5Ͳ/Ͳ) • Between2011Ͳ2012participatedin multiplestudies • Alternatives • LittletonoevidenceofresidualHIV – RemainonPrEPandmonitor fromblood,tissuse,spinalfluid • IfnewHIVinfection– willnotknowifneworearly suppressed? • TheclosestpatienttoanHIV“cure” wehavetoday – Analytictreatmentinterruptionoffalltherapy • Notfeasiblegivenhighriskfrequentsex • Thesmallerthereservoir–thelonger • UnclearlengthoffollowͲuptoassessviralrebound thedelaytoviralreboundoffART Brown AIDS Res Human Retroviruses 2015; Yukl PLoS Pathogens 2013 Case2 HPI • 21yearͲoldLatinomanwhohassexwithmale, • AtPrEPenrollment,neg rapidHIVAb testand cis femaleandtransfemalepartners,onoraldaily HIVRNAneg PrEP – +UrethralGCandtreated • Patientgiven30daysofFTC/TDFwith2refills • Reported“excellentadherence” • Instructedtoreturnq3months • At13ͲmonthPrEPvisit,rapidHIVAb neg • But5dayslater,plasmaHIVRNA=559 copies/mL HPI:PrEPFollowͲUp HPI:PrEPFollowͲUp • Month3:HIVneg (Ab andpooledRNA) • Month10:HIVneg (Ab andpooledRNA) – Reported“good”adherence – Reported“good”adherence – STDtestingneg – STDtestingneg – 3weekslaterreported“lostRx”butreported • Month6:HIVneg (Ab andpooledRNA) adequatesupplyofpillsathomeandreported – ReportedoffPrEPx1mo (unawareofrefills) 100%adherence – Counseledre:adherence,mechanismsforrefills – Newrefillssenttopharmacyandfilled – Treatedfor+UrethralCT,+recurrentHSVͲ2 • Month12:HIVneg (Ab andpooledRNA) – +UrethralGC(urethraldischarge)andtreated – AllotherSTDtestingwasnegative HPI PMH • Month13: • ADHD–wasonmedsuntilprioryear – Reported“excellent”adherence(nomissedpillsin • “Possiblebipolar”–neveronmeds pastweekand1missedpillinpastmonth) • Childhoodasthma – Asymptomatic,nomoreurethraldischarge • STIs– (gonorrhea,chlamydia,HSV)treated – Recentmethamphetamineuseandcondomless receptiveanalsexwithamalepartner severaltimes • (bothfor1sttimein>1year) – ROSneg foranysymptomsc/wARS Meds SocialHx • Truvada qd • BornandraisedintheEastCoast(NY,MD), movedtoBayAreain2016. • Highschooleducation,1yearcollege NKDAbut“thinksmaybeallergictopenicillin” • Currentlyworksasamusicianandatafastfood restaurantpartͲtime • Sexwithmale,cis femaleandtransfemale partners.Usu top;rarelybottom. • “Always”usescondoms • Mostrecentrelationshipwithcis femalebut ended4monthsago. SocialHx FamilyHx • Tobacco:never • Mother:bipolardisease,anemia • ETOH:rarely“doesn’tliketaste” • Father:incarceratedsincepatientwasage3 • Drugs:marijuanaafewtimesaweek,has • 2olderbrothersand1oldersister:allwith triedcocaine,GHB,ecstasy,smokedmeth.No bipolardisease IVDU PhysicalExam Labs at Clinical Visit 15.8 RPR NR • NAD 7.7 308 Hep A NR • NoLAN,OPclear 46.1 Hep B immune • RRR,nom/r/g nl diff Hep C neg • CTAB HLAB5701 neg 139 105 11 • SoftNTND.NoHSM.Norebound. 63 • Testicles,penisuncircumcised.Nolesions.No 4.2 31 0.87 discharge. • Noedema 0.8 Albumin 4.2 HIV 1/2 Ag/Ab pos • Nofocalneuro deficits 20 27 Total protein 7.3 HIV RNA 1544 copies/ml 131 HowWouldYouInterpretTheseResults? HowtoDetermineifThisisPrEPFailure? A. DefinitediagnosisofHIV A. Checkpharmacyrefills B. PossiblediagnosisofHIV B. CheckHIVgenotype C. Hehasafalsepositive C. SendplasmaforARTdrug result leveltesting D. Cannotbedetermined D. Collecthairsamplesfor ARTdrugleveltesting E. Alloftheabove F. Noneoftheabove WhatDoYouthinkistheMostLikelyEtiology ofthePatient’sHIVSeroconversion? PrEPFailureisRARE! A. Exposuretoaviralstrain • Thereareonlyafewcasesreportedworldwide withљsusceptibilitytoTDF – HundredsofthousandsofpeoplehaveusedPrEP and/orFTC – TensofthousandsofHIVinfectionshavebeen B. Inadequateadherenceto prevented. PrEPthatwasnotselfͲ reported – AlmostallpeoplewhousePrEPstayfreeofHIV C. Unrecognizedinfectionat – Ahandfulofothersarediagnosedearlyandpromptly timeofPrEPinitiation andsuccessfullytreated followedbydelayed seroconversion ThemessagetosendyourpatientsisthatPrEPis D. Noneoftheabove highlyhighlyeffective.Thisisdemonstratedbythe rarityofthesePrEPfailurecasesworldwide. GlobalPrEPfailuresͲ Summary WorldwideReportedPrEPFailures • 5casesemtricitabine/tenofivir • AllcompliantwithPrEP • 4multiresistant HIV – 4hadM184VleadingtohighlevelresistancetoFTC – 2virusesthatweresusceptibletoTDF • Highlightaberranciesintestresults – Lowviralloads – Delayedseroconversion,indeterminatewesternblots CohenLancetHIV2018inpress WhatARTRegimenWouldYouStart? CaseContinued A. TDF(orTAF)/FTC+DTG • HIV+testafter13monthsonPrEP B. TDF(orTAF)/FTC+DTG+DRV/r(orc) – ViralLoad559copies/mL – RepeatVLatARTinitiation:1544copies/mL,Ag/Ab pos, C. TDF(orTAF)/FTC/EVG/c+DRV Geenius pos D. TDF(orTAF)+DRV/r(orc) E. ABC/3TC/DTG • Hair: F. TAF/FTC/BIK – TDFadequatelevelsforupto6monthsprior G. TDF/FTC/RPV+DTG • Genotype/Phenotype: H. BorG – RT:L74V,L100I,M184V,K103N I. Noneoftheabove – FTCresistantbutTDFsusceptible(noK65R) SingleͲgenomesequencing APOBECGͲ>A CaseContinued (SGS)ontimepoint2/21/18 Ͳ PBMC • Toevaluateforpossibleearlysuppressed infection P6ͲPRͲRTproviral DNA – SingleGenomeSequencingonearlysample • Limitedviraldiversityconsistentwithacuteinfection %diversity=0.5%includingG>Ahypermutants %diversity=0.1%excludingG>A hypermutants(indicatedearlyinfection) – Additionaltestingofstoredplasmafromthevisit 12weekspriortothediagnosisvisit • NoevidenceofplasmaHIVbyiSCA (lowerlimitof detection=1copyper/ml) APOBECGͲ>A CohenLancetHIV2018inpress 6 nucleotides 80 75 .02 221 8.P BMC .1e 6.C AD-9 5 80 75 .022 21 8.P BMC .1e 6.CA D-7 2 80 75 .02 221 8.P BMC .1e 6.C AD-1 0 80 75 .02 221 8.P BMC .1e 6.C AD-9 80 75 .022 21 8.P BMC .1e 6.CA D-6 6 80 75 .022 21 8.P BMC .1e 6.CA D-3 7 80 75 .022 21 8.P BMC .1e 6.CA D-6 0 80 75 .022 21 8.P BMC .1e 6.CA D-2 1 80 75 .022 21 8.P BMC .1e 6.CA D-1 80 75 .022 21 8.P BMC .1e 6.CA D-6 5 80 75 .022 21 8.P BMC .1e 6.CA D-8 80 75 .022 21 8.P BMC .1e 6.CA D-5 1 80 75 .022 21 8.P BMC .1e 6.CA D-4 4 80 75 .022 21 8.P BMC .1e 6.CA D-8 6 80 75 .022 21 8.P BMC .1e 6.CA D-2 2 80 75 .022 21 8.P BMC .1e 6.CA D-8 2 80 75 .022 21 8.P BMC .1e 6.CA D-6 80 75 .022 21 8.P BMC .1e 6.CA D-2 80 75 .022 21 8.P BMC .1e 6.CA D-9 0 80 75 .022 21 8.P BMC .1e 6.CA D-7 8 80 75 .022 21 8.P BMC .1e 6.CA D-5 4 ComparisontoOtherSF 80 75 .022 21 8.P BMC .1e 6.CA D-5 0 80 75 .022 21 8.P BMC .1e 6.CA D-8 0 SCOPEPID 80 75 .022 21 8.P BMC .1e 6.CA D-5 80 75 .022 21 8.P BMC .1e 6.CA D-1 3 80 75 .022 21 8.P BMC .1e 6.CA D-8 3 80 75 .022 21 8.P BMC .1e 6.CA D-3 3 8075.022218.PBMC.1e6.CAD-74 80 75 .022 21 8.P BMC .1e 6.CA D-5 3 80 75 .022 21 8.P BMC .1e 6.CA D-9 4 8075.022218.PBMC.1e6.CAD-96 8075SGSp6, 80 75 .02 221 8.P BMC .1e 6.C AD-4 1 80 75 .02 221 8.P BMC .1e 6.C AD-7 6 80 75 .02 221 8.P BMC .1e 6.C AD-8 4 EarlyHIVInfectionSamples 8 07 5.02 22 18 .PBM C.1 e6 .CAD -81 8 07 5.02 22 18 .PBM C.1 e6 .CAD -56 8 07 5.02 22 18 .PBM C.1 e6 .CAD -89 80 75 .02 22 18.P BM C.1e 6.C AD -4 0 8 07 5.02 22 18 .PBM C.1 e6 .CAD -46 proͲpol 8075.022218.PBMC.1e6.CAD-61 PID8075HIVDrugResistanceProfile 8075.022218.PBMC.1e6.CAD-18 8075.022218.PBMC.1e6.CAD-73 8075.022218.PBMC.1e6.CAD-47 8075.022218.PBMC.1e6.CAD-23 8075.022218.PBMC.1e6.CAD-88 8075.022218.PBMC.1e6.CAD-36 8075.022218.PBMC.1e6.CAD-68 DemonstratedUnlikely 8075.022218.PBMC.1e6.CAD-12 8075.022218.PBMC.1e6.CAD-11 8075.022218.PBMC.1e6.CAD-26 8075.022218.PBMC.1e6.CAD-14 8075.022218.PBMC.1e6.CAD-70 8075.022218.PBMC.1e6.CAD-3 8075.022218.PBMC.1e6.CAD-57 2 51 2SC OPE 060 51 3-1 .Con tig 1 2 51 2SC OPE 060 51 3-5 .Con tig 1 2 51 2SC OPE 060 51 3-1 3.Co nti g1 Mutation Percentage 2 51 2SC OPE 06 051 3-1 7.Co nti g1 2 51 2SC OPE 060 51 3-2 0.Co nti g1 2 51 2SC OPE 06 051 3-8 .Con tig 1 Contaminant 2 51 2SC OPE 060 51 3-6 .Con tig 1 2 51 2SC OPE 060 51 3-1 8.Co nti g1 2 51 2SC OPE 060 51 3-2 1.Co nti g1 2 51 2SC OPE 060 51 3-1 4.Co nti g1 2 51 2SC OPE 060 51 3-2 2.Co nti g1 2 51 2SC OPE 060 51 3-3 .Con tig 1 Henrich et.al. ofGenomes 2 51 2SC OPE 060 51 3-2 4.Co nti g1 2 51 2SC OPE 060 51 3-1 1.Co nti g1 2 51 2SC OPE 060 51 3-1 9.Co nti g1 2512 2 51 2SC OPE 06 051 3-2 .Con tig 1 2 51 2SC OPE 060 51 3-2 3.Co nti g1 2 51 2SC OPE 060 51 3-4 .Con tig 1 2 51 2SC OPE 060 51 3-1 2.Co nti g1 2 51 2SC OPE 060 51 3-1 5.Co nti g1 PLoS Med2017 2 51 2SC OPE 060 51 3-1 6.Co nti g1 2 51 2SC OPE 060 51 3-9 .Con tig 1 2 51 2SC OPE 060 51 3-1 0.Co nti g1 K65R <1.8% 100 4-0 70 19 8p-2 7 1004-070198p-28 1004-070198p-38 1004-070198p-36 1004-070198p-40 1004-070198p-39 1004-070198p-20 1004-070198p-6 1004-070198p-23 1004-070198p-12 10 04 -070 19 8p -3 K70E <1.8% 1004-070198p-5 1004-070198p-18 1004-070198p-29 1004 1004-070198p-2 1004-070198p-30 1002-082802p-4 1 00 2-08 28 02 p-36 1 00 2-0 828 02 p-4 3 1 00 2-0 828 02 p-1 2 1 00 2-0 828 02 p-1 3 1 00 2-0 828 02 p-1 L100I 100% 1 00 2-0 828 02 p-7 1 00 2-0 828 02 p-8 1 00 2-0 828 02 p-2 1 00 2-0 828 02 p-9 1 00 2-0 828 02 p-1 1 1002 1 00 2-0 828 02 p-5 1 00 2-0 828 02 p-3 1 00 2-0 828 02 p-6 1 00 2-0 828 02 p-1 0 1 00 2-0 828 02 p-3 5 100 6-0 60 101 p-2 4 K103N 100% 100 6-0 60 101 p-8 100 6-0 60 101 p-9 100 6-0 60 101 p-1 9 100 6-0 60 101 p-1 2 100 6-0 60 101 p-2 1 100 6-0 60 101 p-1 3 100 6-0 60 101 p-6 100 6-0 60 101 p-7 100 6-0 60 101 p-1 4 100 6-0 60 101 p-5 100 6-0 60 101 p-3 M184V 100% 100 6-0 60 101 p-2 0 100 6-0 60 101 p-4 100 6-0 60 101 p-1 1006 100 6-0 60 101 p-1 7 1006-060101p-11 1006-060101p-15 1 00 6-06 01 01 p-2 1006-060101p-23 1006-060101p-16 1006-060101p-10 1 005 -02 01 01 p-33 1005-020101p-63 L74V 100% 1005-020101p-56 1005-020101p-25 1005-020101p-29 1005-020101p-58 1005-020101p-39 1005-020101p-36 1005-020101p-40 %Difference 1 00 5-02 01 01 p-70 100 5-0 20 10 1p-5 7 100 5-0 20 10 1p-2 8 1005-020101p-71 D30N 3.6% 1005-020101p-68 100 5-0 20 10 1p-4 2 1005-020101p-45 PID1 PID2 GenRelatedness 100 5-0 20 10 1p-3 4 100 5-0 20 10 1p-2 7 1 00 5-02 01 01 p-50 10 05 -020 10 1p -62 1005 1005-020101p-67 1 005 -02 01 01 p-59 1 005 -02 01 01 p-69 1 005 -02 01 01 p-38 G73S 1.8% 1 005 -02 01 01 p-55 1005-020101p-53 1005-020101p-30 1 005 -02 01 01 p-44 1001 8075 9.4% 1 005 -02 01 01 p-31 1 005 -02 01 01 p-43 1 005 -02 01 01 p-60 1 005 -02 01 01 p-41 1 00 5-02 01 01 p-35 1005-020101p-26 1 00 5-02 01 01 p-51 G48E 5.5% 1002 8075 6.9% 1005-020101p-32 1005-020101p-61 1005-020101p-64 1 00 5-0 20 101 p-5 4 1 00 5-0 20 101 p-3 7 1 00 5-0 20 101 p-6 5 1 00 5-0 20 101 p-6 6 1001-030900p-24 1004 8075 6.6% 1001-030900p-31 1001-030900p-18 1001-030900p-15 1001-030900p-21 1001-030900p-16 1001-030900p-17 1001-030900p-20 1001-030900p-19 1005 8075 7.9% 1001-030900p-23 1001-030900p-38 1001-030900p-45 1001-030900pp-35 1001-030900p-44 1001-030900p-25 1001-030900p-43 1006 8075 8.3% 1001-030900p-27 1001 1001-030900p-29 1001-030900p-26 1001-030900p-42 1001-030900p-28 1001-030900p-30 1001-030900p-33 1001-030900p-37 2512 8075 7.4% 1001-030900p-41 1001-030900p-36 1001-030900p-34 1001-030900p-40 1001-030900p-32 HIV1B p6pol pNL4-3P6-RT 10 SubtypeBref,NL4Ͳ3 - STAT PAK neg - STAT PAK neg - STAT PAK neg - STAT PAK neg - Pooled RNA neg - Pooled RNA neg - Pooled RNA neg - Pooled RNA neg - Urine GC pos - 3 Partners - Urine GC pos - iSCA neg - Urine GC pos -3 Partners - 4 Partners -2 Partners - Genital HSV-2 PCR pos - STAT PAK neg CaseSummary - 4 Partners - Pooled RNA POS (529 copies/mL) - Urine GC POS - 5 Partners -Ag/AbPOS • HIVacquisitionestimatedtooccur~21Ͳ28days -GeeniusPOS - HIV RNA 1,544 copies/mL - SGS limited viral diversity priortodiagnosisbasedon: - HIV RNA <40 – Thetimingofexposuretohislikelytransmission Testing copies/mL Highadherencebyhair partner – Thelackofgeneticdiversityoftheproviral population Highadherence – HighlevelsofadherencebyselfͲreport,DBSandhair byDBS measures 0 3 6 10 12 13 13.3 14 • ThisistheSIXTH reportedcaseworldwideof potentialPrEPfailureandcontributestothese limiteddata. Months Acknowledgements UCSFTreatAcuteHIVStudy Case2:StephanieCohen,Darpun Sachdev,Oliver Bacon,MaryKearney,SusaCoffey,BobGrant, DianeHavlir,MonicaGandhi PAGER:415Ͳ443Ͳ5035 Case1&2:SCOPETEAM [email protected] JeffMartin RickHecht Studycoordinators [email protected] [email protected] TimHenrich KaraMarson StudyPI Top: Enrique MartinezͲOrtiz, Viva Tai, Chris Pilcher, Mike Busch, Steven Deeks, Peter Hunt. Bottom: Monika Deswal, Montha Pao, Maya BallͲBurack, Rebecca Hoh, 415Ͳ735Ͳ5127 Heather Hartig, Marian Kerbleski, Sulggi Lee. Not pictured: Raeni Miller, Claire Rappaport, Melissa Krone, Mary Ellen Kelly, Elnaz Eilkhani LisaHarms TonyLing [email protected] ϭϭͬϮϳͬϮϬϭϴ KƵƚůŝŶĞŽĨƚĂůŬ ZĞǀŝĞǁŶĞǁĂŶƚŝƌĞƚƌŽǀŝƌĂůŵĞĚŝĐĂƚŝŽŶƐ ƌĞĐĞŶƚůLJĂƉƉƌŽǀĞĚ͕ŝŶĐůƵĚŝŶŐƐŝŶŐůĞƉŝůů ĐŽŵďŝŶĂƚŝŽŶƐ ^ƚĂƚĞŽĨƚŚĞƌƚŽŶZd dǁŽŶĞǁŵĞĚŝĐĂƚŝŽŶƐŚĞƌĞŽƌĐůŽƐĞĨŽƌ ǀĞƌLJĞdžƉĞƌŝĞŶĐĞĚƉĂƚŝĞŶƚƐ ZĞǀŝĞǁŶĞǁƉĂƌĂĚŝŐŵƐŝŶ,/sŵĞĚŝĐŝŶĞ DĞĚŝĐĂůDĂŶĂŐĞŵĞŶƚŽĨ/^͕D ĐŽƵƌƐĞ dǁŽĚƌƵŐƚŚĞƌĂƉLJ ĞĐĞŵďĞƌϲ͕ϮϬϭϴ ^ǁŝƚĐŚĞƐ ĂƌƌŝĞƌƐƚŽƌĞƐŝƐƚĂŶĐĞ WƌĞĚŝĐƚŽƌƐŽĨĚŽŝŶŐǁĞůůŽŶϮͲĚƌƵŐƚŚĞƌĂƉLJ DŽŶŝĐĂ'ĂŶĚŚŝD͕DW, ;/ŶũĞĐƚĂďůĞƐͲ ŶĞdžƚLJĞĂƌͿ DĞĚŝĐĂůĚŝƌĞĐƚŽƌ͕tĂƌĚϴϲ,/sůŝŶŝĐ сŝǀŝƐŝŽŶŽĨ,/s͕/ŶĨĞĐƚŝŽƵƐŝƐĞĂƐĞƐ͕ĂŶĚ'ůŽďĂůDĞĚŝĐŝŶĞ ;EŽĨŝŶĂŶĐŝĂůĚŝƐĐůŽƐƵƌĞƐͿ ĂƐĞηϭ Z^͗tŚĂƚŝƐƚŚĞƌĞŐŝŵĞŶLJŽƵǁŽƵůĚĐŚŽŽƐĞ ϱϮLJŽ ŵĂŶĚŝĂŐŶŽƐĞĚǁŝƚŚ,/sϯϬLJĞĂƌƐĂŐŽ ĨŽƌƚŚŝƐƉĂƚŝĞŶƚ͍ dͬϯdƚŚĞŶdͬϯdͬŶĞǀŝƌĂƉŝŶĞƚŚĞŶd&ͬ&dнĞĨĂǀŝƌĞŶnj ŝŶ ϮϬϬϮ;ĂŶĚƐŝŶŐůĞƉŝůůĐŽŵďŝŶĂƚŝŽŶŝŶϮϬϬϳͿ ϭ͘ /ͬd&ͬ&d Ϯ͘ ZsͬĐŽďŝͬd&ͬ&d ,ĂĚŽĨĨͲĂŶĚͲŽŶƉƌŽďůĞŵƐǁŝƚŚĂĚŚĞƌĞŶĐĞĂŶĚǀŝƌĂůůŽĂĚ 'ĞŶŽƚLJƉĞƐŚŽǁƐ ϯ͘ ZsͬĐŽďŝͬd&ͬ&dнĚŽƌĂǀŝƌŝŶĞ ĚĞƚĞĐƚĂďŝůŝƚLJŽǀĞƌƚŝŵĞǁŝƚŚĞŵĞƌŐĞŶĐĞŽĨDϭϴϰs͕<ϭϬϯE͕zϭϴϭ͕ zϭϴϭ͕<ϭϬϯE͕ 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ďŝŽŵĂƌŬĞƌƐ͕ďƵƚǁĂƐďĞŶĞĨŝƚŝŶďŽŶĞ WĞƌƉĂĐŬĂŐĞŝŶƐĞƌƚ͗ϳƐƵďũĞĐƚƐŚĂĚŚͬŽd&Ͳ ĞǀĞŶŝŶƐĞƚƚŝŶŐŽĨůŽƚƐŽĨƉƌŝŽƌĞdžƉĞƌŝĞŶĐĞ;ŽŶůLJ ďŝŽŵĂƌŬĞƌƐ ĂƐƐŽĐŝĂƚĞĚƌĞƐŝƐƚĂŶĐĞŵƵƚĂƚŝŽŶƐ͖ϱϯŚĂĚŚͬŽ ĞdžĐůƵĚĞĚD^͖ĂůůŽǁĞĚd&͕ϯdƌĞƐŝƐƚĂŶĐĞͿ ϯd;ŵĂŝŶůLJDϭϴϰͿ͘ůůƐƵƉƉƌĞƐƐĞĚ ϭ Ϯ KƌŬŝŶ ĞƚĂů͕>ĂŶĐĞƚ,/s͕ϮϬϭϴ͖ ƌŽŶ:ZK/ϮϬϭϴ͖ ƌŽŶ:/ǁĞĞŬϮϬϭϴ <ĂŬƵĚĂd͘:ϮϬϭϰ͖ KƌŬŝŶ>ĂŶĐĞƚ,/sϮϬϭϴ;ĚĂƌƵŶĂǀŝƌƉĂĐŬĂŐĞŝŶƐĞƌƚͿ ϰ ϭϭͬϮϳͬϮϬϭϴ ŽƌĂǀŝƌŝŶĞ ;нͬͲd&ͬϯdͿĂƉƉƌŽǀĞĚƵŐƵƐƚϯϬ͕ϮϬϭϴ Z/s , ʹ ƚŚŝŶŬ͞ŚĞĂĚͲƚŽͲŚĞĂĚ͟ǁŝƚŚ 3526 &216 ĂŶŽƚŚĞƌEEZd/ >ŽǁŝƐŚ ŐĞŶĞƚŝĐďĂƌƌŝĞƌ DƵůƚŝĐĞŶƚĞƌ͕ƌĂŶĚŽŵŝnjĞĚ͕ĚŽƵďůĞͲďůŝŶĚƉŚĂƐĞ///ŶŽŶŝŶĨĞƌŝŽƌŝƚLJ ƚƌŝĂůϭ tĞůůƚŽůĞƌĂƚĞĚ ƚŽƌĞƐŝƐƚĂŶĐĞůŝŬĞĂůů ^ƚƌĂƚŝĨŝĞĚďLJ,/sͲϭZE;хǀƐчϭϬϬ͕ϬϬϬĐŽƉŝĞƐͬŵ>Ϳ͕ WƌŝŵĂƌLJŶĂůLJƐŝƐ /ǁĞĞŬ K<ŝŶŚĞƉĂƚŝĐĂŶĚ ĐŚƌŽŶŝĐ,sŽƌ,sĐŽŝŶĨĞĐƚŝŽŶƐƚĂƚƵƐ tŬϰϴ ŶĂůLJƐŝƐ EEZd/Ɛ;ĞŵĞƌŐŝŶŐ tŬϵϲ ƌĞŶĂůĨĂŝůƵƌĞ ƌĞƐŝƐƚĂŶƚŵƵƚĂƚŝŽŶ KZͬϯdͬd&ϭϬϬͬϯϬϬͬϯϬϬŵŐYн EŽĨŽŽĚƌĞƋƵŝƌĞŵĞŶƚƐ sϭϬϲͿ dƌĞĂƚŵĞŶƚͲŶĂŝǀĞĂĚƵůƚƐǁŝƚŚ &sͬ&dͬd&WůĂĐĞďŽ ;Ŷ сϯϲϰͿ tŽƌŬƐĂŐĂŝŶƐƚzϭϴϭ ^ŝŶŐůĞƉŝůůĐŽŵďŝŶĂƚŝŽŶ ,/sͲϭZEшϭϬϬϬĐŽƉŝĞƐͬŵ> KƉĞŶͲůĂďĞůĞdžƚĞŶƐŝŽŶ ĂŶĚŶŽƌĞƐŝƐƚĂŶĐĞƚŽƐƚƵĚLJĚƌƵŐƐ &sͬ&dͬd&ϲϬϬͬϮϬϬͬϯϬϬŵŐYн ĨŽƌϵϲǁŬƐ E<ϭϬϯE;ĂŶĚ ŝƐǁŝƚŚd&ͬϯd ;EсϳϮϴͿ KZͬϯdͬd&WůĂĐĞďŽ 'ϭϵϬͿĐŽŶƚĂŝŶŝŶŐ ĂŶ͛ƚƵƐĞǁŝƚŚ ;Ŷ сϯϲϰͿ ǀŝƌƵƐĞƐ ƌŝĨĂŵƉŝŶ;ĐĂŶĚŽƵďůĞ ĚŽƐĞǁŝƚŚƌŝĨĂďƵƚŝŶͿ WƌŝŵĂƌLJĞŶĚƉŽŝŶƚ͗,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>ĂƚtŬ ϰϴ;ŶŽŶŝŶĨĞƌŝŽƌŝƚLJ ŵĂƌŐŝŶ͗ͲϭϬйͿϮ DŽůŝŶĂ:D͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚ>W Ϭϭϳ͖>ĂŝDͲd͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚd,WϭϬϭ͖DŽůŝŶĂ:D͕>ĂŶĐĞƚ,/s ϮϬϭϴ͖Ϯ͘^ƋƵŝƌĞƐ< ͕ĞƚĂů͘/^ϮϬϭϳ͘ďƐƚƌĂĐƚdhϬϭϬϰ>͖^ƋƵŝƌĞƐ</ǁĞĞŬϮϬϭϴ>ϭ͖<ƵŵĂƌW/ǁĞĞŬϮϬϭϴ>Ϯ ϭ͘DŽůŝŶĂ:D͕>ĂŶĐĞƚ,/sϮϬϭϴ͖Ϯ͘KƌŬŝŶ ͘/ϮϬϭϴ͘ ϯ͘^ƋƵŝƌĞƐ<͕/ǁĞĞŬϮϬϭϴ Z/s Ͳ, ͗<ĞLJ ĨĨŝĐĂĐLJ&ŝŶĚŝŶŐƐ Z/s Ͳ&KZtZ͗EZd/Ɛн ŝƚŚĞƌŽƌĂǀŝƌŝŶĞŽƌZsͬZds &^ŶĂƉƐŚŽƚŶĂůLJƐŝƐ 2XWFRPHDW:N KZͬϯdͬd&;Ŷ &sͬ&dͬd& ŝŶdƌĞĂƚŵĞŶƚͲEĂŝǀĞĚƵůƚƐ;W/с&KZtZͿ Q сϯϲϰͿ ;ŶсϯϲϰͿ ϭϬϬ dƌĞĂƚŵĞŶƚĚŝĨĨĞƌĞŶĐĞ͗ DƵůƚŝĐĞŶƚĞƌ͕ƌĂŶĚŽŵŝnjĞĚ͕ĚŽƵďůĞͲďůŝŶĚƉŚĂƐĞ///ƐƚƵĚLJϭ Ws& ϮϮ;ϲ͘ϬͿ ϭϰ;ϯ͘ϴͿ ϯ͘ϴй;ϵϱй/͗ͲϮ͘ϰйƚŽϭϬ͘ϬйͿ ^ƚƌĂƚŝĨŝĞĚďLJ,/sͲϭZE;хǀƐчϭϬϬ͕ϬϬϬĐŽƉŝĞƐͬŵ>Ϳ WƌŝŵĂƌLJŶĂůLJƐŝƐ ƵƌƌĞŶƚŶĂůLJƐŝƐ 'ĞŶŽƚLJƉĞĚ Ϯϯ Ϯϰ ϳϳ͘ϱ ϳϯ͘ϲ ĂŶĚEZd/ƐĞůĞĐƚŝŽŶ;d&ͬ&dŽƌͬϯdͿ tŬϰϴ tŬϵϲ ϴϬ WƌŝŵĂƌLJEEZd/Ύ ϲ;ϭ͘ϲͿ ϭϮ;ϯ͘ϯͿ ƌĞƐŝƐƚĂŶĐĞ ŽƌĂǀŝƌŝŶĞϭϬϬŵŐYнϮEZd/ƐΎ ϲϬ WƌŝŵĂƌLJEZd/Ύ ZdͲŶĂŝǀĞĂĚƵůƚƐǁŝƚŚ,/sͲϭ нZsͬZdsWůĂĐĞďŽ ƌĞƐŝƐƚĂŶĐĞ ZEшϭϬϬϬĐŽƉŝĞƐͬŵ>ǁŝƚŚŝŶ ;ŶсϯϴϯͿ ϰϱĚĂLJƐ͖ŶŽƌĞƐŝƐƚĂŶĐĞƚŽ KƉĞŶͲůĂďĞůĞdžƚĞŶƐŝŽŶ ϰϬ ĨŽƌϵϲǁŬƐΏ WƌŝŵĂƌLJEEZd/ƌĞƐŝƐƚĂŶĐĞŵƵƚĂƚŝŽŶƐ͕ ƐƚƵĚLJĚƌƵŐƐďLJŐĞŶŽƚLJƉĞƚĞƐƚ ZsͬZdsϴϬϬͬϭϬϬŵŐYнϮEZd/ƐΎ KZͬϯdͬd&͗zϭϴϴ>͖sϭϬϲ/͕&ϮϮϳ͖,ϮϮϭ,ͬz͕͖͕ ;EсϳϲϲͿ нŽƌĂǀŝƌŝŶĞWůĂĐĞďŽ ϮϬ WϮϮϱ,͕zϯϭϴzͬ&͖ &sͬ&dͬd&͗<ϭϬϯE͕ ϭϯϴ ͬ'͖ ;ŶсϯϴϯͿ ,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>;йͿ 'ϭϵϬ ͖DϮϯϬ>͖'ϭϵϬ ͕<ϭϬϭ<ͬE͕WϮϮϱWͬ, Ύ/ŶǀĞƐƚŝŐĂƚŽƌĐŚŽŝĐĞƉƌŝŽƌƚŽƌĂŶĚŽŵŝnjĂƚŝŽŶŽĨŽƉĞŶͲůĂďĞůd&ͬ&dŽƌͬϯd͘ Ϭ ΎWƌŝŵĂƌLJEZd/ƌĞƐŝƐƚĂŶĐĞŵƵƚĂƚŝŽŶƐ͕ ΏKƉƚŝŽŶĨŽƌĞůŝŐŝďůĞƉĂƌƚŝĐŝƉĂŶƚƐƚŽƌĞĐĞŝǀĞĚŽƌĂǀŝƌŝŶĞнϮEZd/ƐŝŶĞdžƚĞŶƐŝŽŶƉŚĂƐĞ͘ KZͬϯdͬd& &sͬ&dͬd& KZͬϯdͬd&͗Dϰϭ>͕Dϭϴϰs͖<ϲϱZ͖ &sͬ&dͬd&͗sϭϭϴ/͕Dϭϴϰs͖<Ϯϭϵ<ͬ ͖<ϲϱ<ͬZ ŽƚƚŽŵůŝŶĞ͗EŽĚŝĨĨĞƌĞŶĐĞŝŶĞĨĨŝĐĂĐLJ WƌŝŵĂƌLJĞŶĚƉŽŝŶƚ͗,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>ĂƚtŬϰϴϮ ϭ͘DŽůŝŶĂ:D͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚ >W Ϭϭϳ͘Ϯ͘DŽůŝŶĂ:D͕ĞƚĂů͘ZK/ϮϬϭϳ͘ďƐƚƌĂĐƚϰϱ> ^ƋƵŝƌĞƐ< ͕/tĞĞŬϮϬϭϴĂŶĚKƌŬŝŶ ͘/ϮϬϭϴ͘ ϱ ϭϭͬϮϳͬϮϬϭϴ Z/s Ͳ&KZtZĂŶĚZ/s Ͳ, ͗ϳĨĂŝůĞĚǁŝƚŚ Z/s Ͳ&KZtZ͗sŝƌŽůŽŐŝĐKƵƚĐŽŵĞƐĂƚtŬϵϲ ƌĞƐŝƐƚĂŶĐĞ ,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>ďLJ &^ŶĂƉƐŚŽƚŶĂůLJƐŝƐ KZ ZsͬZds ^ƵƐĐĞƉƚŝďŝůŝƚLJĂŶĂůLJƐŝƐŽĨƚŚĞϳĚŽƌĂǀŝƌŝŶĞͲƌĞƐŝƐƚĂŶƚŵƵƚĂŶƚƐĨƌŽŵZ/s Ͳ KďƐĞƌǀĞĚ&ĂŝůƵƌĞŶĂůLJƐŝƐ͕й;ŶͿΎ ϭϬϬ dƌĞĂƚŵĞŶƚŝĨĨĞƌĞŶĐĞ͗ &KZtZ;ϮͿĂŶĚZ/s Ͳ, ;ϱͿƉŚĂƐĞϯƐƚƵĚŝĞƐ;sϭϬϲ͕,ϮϮϭ͕&ϮϮϳͿ ůůƉĂƌƚŝĐŝƉĂŶƚƐ ϴϭ͘Ϭ;ϯϰϮͿ ϳϲ͘ϴ;ϯϮϯͿ ϳ͘ϭй;ϵϱй/͗Ϭ͘ϱйƚŽϭϯ͘ϳйͿ >,/sͲϭZE͕ĐŽƉŝĞƐͬŵ> &ŽůĚŚĂŶŐĞďLJsŝƌƵƐ EZd/ EEZd/ ϴϬ ϳϯ͘ϭ чϭϬϬ͕ϬϬϬ ϴϱ͘ϲ;ϮϲϰͿ ϳϵ͘ϳ;ϮϴϮͿ ϲϲ͘Ϭ хϭϬϬ͕ϬϬϬ ϲϱ͘ϰ;ϳϴͿ ϲϱ͘Ϯ;ϳϮͿ s Ěϰd ĚĚ/ &d ϯd d&s KZ &s dZ ZWs чϱϬϬ͕ϬϬϬ ϴϭ͘ϴ;ϯϮϱͿ ϳϴ͘ϭ;ϯϭϭͿ td ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϭ͘Ϭ ϲϬ хϱϬϬ͕ϬϬϬ ϲϰ͘ϳ;ϭϳͿ ϯϲ͘ϰ;ϭϭͿ ϵϴ'ͬ&ϮϮϳͬDϭϴϰs Ϭ͘ϭ Ϭ͘ϳ ϭ͘Ϯ Ϯ͘ϳ хϭϬϬ хϭϬϬ Ϭ͘ϱ хϵϯ ϵ͘Ϭ Ϯ͘ϴ ϯ͘ϴ >ϰнĐĞůůĐŽƵŶƚ͕ĐĞůůƐͬŵŵϯ ϵϴ'ͬsϭϬϲ/ͬ,ϮϮϭzͬ&ϮϮϳͬ чϱϬ ϴϬ͘Ϭ;ϱͿ ϱϮ͘ϵ;ϭϳͿ Ϭ͘ϭ Ϭ͘ϲ ϭ͘Ϯ ϯ͘Ϯ хϭϬϬ хϭϬϬ Ϭ͘ϲ хϭϭϬ ϭϵ ϳ͘ϵ ϭϬ ϰϬ Dϭϴϰs ϱϭͲϮϬϬ ϳϭ͘Ϭ;ϯϭͿ ϲϱ͘ϴ;ϯϴͿ хϮϬϬ ϴϮ͘Ϭ;ϯϬϲͿ ϳϵ͘ϵ;ϮϲϴͿ sϭϬϲͬWϮϮϱ,ͬzϯϭϴ&ͬ<ϲϱZ ϭ͘Ϭ ϭ͘ϰ ϭ͘ϴ Ϯ͘ϰ ϳ͘ϳ ϭϮ ϭ͘ϲ хϮϭϬ ϰ͘ϴ Ϭ͘ϳ ϭ͘Ϭ ϮϬ EZd/ sϭϬϲ/ͬ&ϮϮϳ Ϭ͘Ϯ Ϭ͘ϳ ϭ͘Ϭ Ϭ͘ϳ Ϯ͘ϴ ϯ͘ϭ Ϭ͘ϯ хϭϬϱ Ϯ͘ϱ ϰ͘Ϭ ϯ͘ϰ ,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>;йͿ ϮϴϬͬ ϮϱϮͬ d&ͬ&d ϴϬ͘ϯ;ϮϵϱͿ ϳϲ͘ϯ;ϮϴϯͿ sϭϬϲ/ͬ,ϮϮϭzͬ&ϮϮϳͬDϭϴϰs Ϭ͘Ϯ Ϭ͘ϴ ϭ͘ϭ ϯ͘ϵ хϭϬϬ хϭϬϬ Ϭ͘ϰ хϵϲ ϭ͘ϳ ϭ͘ϱ ϭ͘Ϯ ŶͬEс ϯϴϯ ϯϴϯ ͬϯd ϴϱ͘ϭ;ϰϳͿ ϴϬ͘Ϭ;ϰϬͿ Ϭ sϭϬϲDͬ&ϮϮϳͬ<ϲϱZͬDϭϴϰs Ϭ͘ϭ Ϭ͘ϱ ϭ͘ϱ Ϯ͘ϴ хϭϬϬ хϭϬϬ Ϭ͘ϰ хϵϴ ϭϭ͘Ϭ Ϭ͘ϲ Ϭ͘ϰ KZ ZsͬZdsн ΎŝƐĐŽŶƚŝŶƵĂƚŝŽŶĨŽƌůĂĐŬŽĨĞĨĨŝĐĂĐLJĐŽŶƐŝĚĞƌĞĚĨĂŝůƵƌĞ͕ŽƚŚĞƌŵŝƐƐŝŶŐ zϭϴϴ>ͬDϭϴϰs Ϭ͘ϱ Ϭ͘ϴ ϭ͘ϲ Ϯ͘ϵ хϭϬϬ хϭϬϬ Ϭ͘ϴ хϭϴϭ хϭϮϬ ϯ͘ϰ ϭϭ нϮEZd/Ɛ ϮEZd/Ɛ ĚĂƚĂĞdžĐůƵĚĞĚ͖ŶƌĞĨĞƌƐƚŽƚŽƚĂůŶƵŵďĞƌŽĨƉĂƌƚŝĐŝƉĂŶƚƐƉĞƌƐƵďŐƌŽƵƉ͘ KƌĂŶŐĞƐŚĂĚŝŶŐĚĞŶŽƚĞƐƌĞƐŝƐƚĂŶĐĞ͘'ƌĞĞŶƐŚĂĚŝŶŐĚĞŶŽƚĞƐƐƵƐĐĞƉƚŝďŝůŝƚLJ͘ŽůĚĞĚŝƚĂůŝĐƐŝŶĚŝĐĂƚĞƉĂƌƚŝĂůƐĞŶƐŝƚŝǀŝƚLJ͘ DŽůŝŶĂ:D͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚ>W Ϭϭϳ͘ >ĂŝDͲd͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚd,WϭϬϭ͘ Z/s Ͳ^,/&d͗^ǁŝƚĐŚƚŽKZͬϯdͬd&ǀƐŽŶƚŝŶƵĂƚŝŽŶ Z/s Ͳ^,/&d͗ ĨĨŝĐĂĐLJŽĨ^ǁŝƚĐŚƚŽKZͬϯdͬd& ŽĨĂƐĞůŝŶĞZdŝŶsŝƌŽůŽŐŝĐĂůůLJ^ƵƉƉƌĞƐƐĞĚĚƵůƚƐ DƵůƚŝĐĞŶƚĞƌ͕ƌĂŶĚŽŵŝnjĞĚ͕ŽƉĞŶͲůĂďĞůƉŚĂƐĞ///ŶŽŶŝŶĨĞƌŝŽƌŝƚLJƚƌŝĂů tŬϮϰ tŬϰϴ ĚƵůƚƐǁŝƚŚ,/sͲϭZE KZͬϯdͬd&Ύ KZͬϯdͬd&Ύ фϰϬĐŽƉŝĞƐͬŵ>͕ƐƚĂďůĞZd ;ŶсϰϰϳͿ ;ŶсϰϮϳͿ ĨŽƌшϲŵŽƐǁŝƚŚŶŽƉƌŝŽƌ ǀŝƌŽůŽŐŝĐĨĂŝůƵƌĞŽƌ ĂƐĞůŝŶĞZdΏ KZͬϯdͬd&Ύ ƌĞƐŝƐƚĂŶĐĞƚŽƐƚƵĚLJĚƌƵŐƐ͕ ;ŶсϮϮϯͿ ;ŶсϮϬϵͿ ĂŶĚĞ'&ZшϱϬŵ>ͬŵŝŶ ;EсϲϳϬͿ ΎKZͬϯdͬd&ĚŽƐŝŶŐ͗ϭϬϬͬϯϬϬͬϯϬϬŵŐY͘ ΏϮEZd/ƐнZdsͲ ŽƌK/ͲƐƚĞĚW/;ds͕Zs͕>WsͿ͕ s'ͬK/͕ŽƌEEZd/; &s͕EsW͕ZWsͿ͘ WƌŝŵĂƌLJĞŶĚƉŽŝŶƚ͗,/sͲϭZEфϱϬĐŽƉŝĞƐͬŵ>;&^ŶĂƉƐŚŽƚͿ EŽĞǀŝĚĞŶĐĞŽĨƚƌĞĂƚŵĞŶƚͲĞŵĞƌŐĞŶƚƌĞƐŝƐƚĂŶĐĞŝŶƉĂƚŝĞŶƚƐƌĞĐĞŝǀŝŶŐKZͬϯdͬd& <ƵŵĂƌ͘/tĞĞŬϮϬϭϴ͘ďƐƚƌ>Ϯ͘ <ƵŵĂƌ͘/tĞĞŬϮϬϭϴ͘ďƐƚƌ>Ϯ͘ ϲ ϭϭͬϮϳͬϮϬϭϴ ŽƚƚŽŵůŝŶĞŽŶĚŽƌĂǀŝƌŝŶĞ ĂƐĞηϭͲ ŵŽĚŝĨŝĞĚ EŽŶĞŽĨƚŚĞEEZd/ƐĂƌĞĨŝƌƐƚͲůŝŶĞŝŶƚŚĞh͘^͘ ϱϮLJŽ ŵĂŶĚŝĂŐŶŽƐĞĚǁŝƚŚ,/sϯϬLJĞĂƌƐĂŐŽ ZĞƉůĂĐĞŵĞŶƚŽĨ &sͬd&ͬϯdǁŝƚŚKZͬd&ͬϯd ŝŶƚĞƌŶĂƚŝŽŶĂůůLJĚĞƉĞŶĚƐŽŶĐŽƐƚ dͬϯdƚŚĞŶdͬϯdͬŶĞǀŝƌĂƉŝŶĞƚŚĞŶd&ͬ&dн ĨĂǀŝƌĞŶnj ŝŶϮϬϬϮ;ĂŶĚ ƐŝŶŐůĞƉŝůůĐŽŵďŝŶĂƚŝŽŶŝŶϮϬϬϳͿ /ŶŽƵƌƐĞƚƚŝŶŐ ,ĂĚŽĨĨͲĂŶĚͲŽŶƉƌŽďůĞŵƐǁŝƚŚĂĚŚĞƌĞŶĐĞĂŶĚǀŝƌĂůůŽĂĚĚĞƚĞĐƚĂďŝůŝƚLJŽǀĞƌ WĂƚŝĞŶƚƐǁŝƚŚŽƵƚƌĞƐŝƐƚĂŶĐĞ͗ZWsͬd&ͬ&dƵƐĞĚĂƐĂůƚĞƌŶĂƚŝǀĞ͖ ƚŝŵĞǁŝƚŚĞŵĞƌŐĞŶĐĞŽĨDϭϴϰs͕<ϭϬϯE͕zϭϴϭ͕ϲϳEĂŶĚƐǁŝƚĐŚĞĚƚŽ Z>ͬ dZͬd&ͬ&dŝŶϮϬϬϴ;ĚĞĐůŝŶĞĚW/Ϳ KZͬd&ͬϯdŚĂƐd&ĂŶĚŶŽƚd&͖KZͬd&ͬ&dĐŽƵůĚĞůŝŵŝŶĂƚĞ ĨŽŽĚĐŽŶĐĞƌŶƐďƵƚŶŽƚƐŝŶŐůĞƉŝůů /ŶϮϬϭϬ͕ǁŝƚŚŵƵůƚŝƉůĞĨĂŝůƵƌĞƐ͕ƐǁŝƚĐŚĞĚƚŽZsͬƌͬd&ͬ&d͕ƚŚĞŶ ƌŝůƉŝǀŝƌŝŶĞ ĂĚĚĞĚŝŶϮϬϭϯĂƐŽŶŐŽŝŶŐǀŝƌĞŵŝĂ͕ƚŚĞŶd'/ĂĚĚĞĚŝŶϮϬϭϱ͘ WĂƚŝĞŶƚƐǁŝƚŚƌĞƐŝƐƚĂŶĐĞ͗ ƚƌĂǀŝƌŝŶĞ ŽƌƌŝůƉŝǀŝƌŝŶĞ ƵƐĞĚŝŶĂdZ/KůŝŬĞ WƚŶĞǀĞƌƌĞĂůůLJƐƵƉƉƌĞƐƐĞĚĂŶĚŶŽǁŐĞŶŽƚLJƉĞƐŚŽǁƐŵƵůƚŝƉůĞEZd/ ƌĞŐŝŵĞŶ;EZ^ϭϯϵͿϮ ǁŚŝĐŚǁĂƐ 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Ύ&ŽƌƚŚĞƐĞϯƉĂƚŝĞŶƚƐ͕,/sͲϭZEĂƚůĂƐƚŵĞĂƐƵƌĞŵĞŶƚ͗фϱϬĐŽƉŝĞƐͬŵ>͕ϱϱĐŽƉŝĞƐͬŵ>͕ϯϬϬĐŽƉŝĞƐͬŵ>͕ƌĞƐƉĞĐƚŝǀĞůLJ͘ ďŽƵĚD͕ĞƚĂů͘/^ϮϬϭϴ͘ďƐƚƌĂĐƚd,W Ϭϰϳ͘ ĂŚŶW͕ĞƚĂů͘dŚĞ >ĂŶĐĞƚ͘EŽǀĞŵďĞƌ ϮϬϭϴ ϭϬ ϭϭͬϮϳͬϮϬϭϴ ' D/E/ͲϭĂŶĚͲϮ͗sŝƌŽůŽŐŝĐZĞƐƉŽŶƐĞĂƚtŬϰϴ;ĂůƐŽ EZ^ϭϲϳ>D/K>͗d'ͬϯdƐǁŝƚĐŚŝŶĞdžƉĞƌŝĞŶĐĞĚƉĂƚŝĞŶƚƐ;ϭϬϰ ƉĂƚŝĞŶƚƐĂĨƚĞƌŵĞĚŝĂŶϰ͘ϱLJĞĂƌƐŽŶZd͖ǀů фϱϬͿ ƐƚƌĂƚŝĨŝĞĚďLJϰͬǀŝƌĂůůŽĂĚͿ /ŶƉĂƌƚŝĐŝƉĂŶƚƐǁŝƚŚϰфϮϬϬϱϬ;ϳϵйͿŽĨϲϯŽŶϮͲĚƌƵŐƐĂĐŚŝĞǀĞĚ ,/sZEфϱϬĐŽŵƉĂƌĞĚǁŝƚŚϱϭ;ϵϯйͿŽĨϱϱŽĨƚŚŽƐĞŽŶϯͲĚƌƵŐƐ͘ DŽƐƚƌĞĂƐŽŶƐĐŝƚĞĚǁĞƌĞŶŽŶͲĞĨĨŝĐĂĐLJƌĞůĂƚĞĚʹ ƉƌŽƚŽĐŽůǀŝŽůĂƚŝŽŶ͕ sŝƌŽůŽŐŝĐKƵƚĐŽŵĞƐďLJ&^ŶĂƉƐŚŽƚŶĂůLJƐŝƐ ůŽƐƐƚŽĨŽůůŽǁͲƵƉ͕ĞƚĐ͘;dĂďůĞϰŝŶƉĂƉĞƌͿ ϯƉĂƚŝĞŶƚƐĚŝĚŶ͛ƚƐƚĂLJфϱϬďLJǁŬ ϰϴ͗ ϭůŽƐƚƚŽĨŽůůŽǁͲƵƉ͖ϮǁŝƚŚǀŝƌŽůŽŐŝĐ ϵϯ ϵϯ ϵϰ ϭϬϬ ϵϭ ϵϰ ϵϮ ϵϯ ϵϯ ϵϯ ϭϬϬ ϵϭ /ddͲ ϵϬ ĨĂŝůƵƌĞʹ ϭϮĂŶĚϰϴǁĞĞƐͿ ϴϬ ϳϵ ϴϬ WWΎ WƚǁŚŽĨĂŝůĞĚǁĞĞŬϭϮͲ ŚĂĚďĞĞŶŽŶ ϲϬ ϲϬ Z>ͬͬϯdŝŶƉĂƐƚĂŶĚƐǁŝƚĐŚĞĚ ϰϬ ƚŽZ>ͬ dZĐŽŶƚĂŝŶŝŶŐƌĞŐŝŵĞŶ ϰϬ d'нϯd d'нd&ͬ&d ,/sͲϭZE WĂƚŝĞŶƚƐtŝƚŚ ϮϬ WĂƚŝĞŶƚǁŚŽĨĂŝůĞĚϰϴʹ ǁĂƐŽŶ фϱϬĐŽƉŝĞƐͬŵ>;йͿ ϮϬ ϱϮϲͬ ϱϯϭͬ ϭϮϵͬ ϭϯϴͬ ϲϬϱͬ ϲϭϴͬ ϱϬͬ ϱϭͬ ϲ ϱ ϱ ,/sͲϭZEфϱϬĐͬŵ>;йͿ ŶͬEс ϯ Ϯ Ϯ ϰ ϱϳϲ ϱϲϰ ϭϰϬ ϭϱϯ ϲϱϯ ϲϲϮ ϲϯ ϱϱ d&ͬ&dͬ &sŽƌZWsŝŶƉĂƐƚ͕ ϭ Ϭ Ϭ чϭϬϬ͕ϬϬϬ !ϭϬϬ͕ϬϬϬ !ϮϬϬ чϮϬϬ ĚĞǀĞůŽƉĞĚ>ϳϰ>ŝŶ>D/K>͕ sŝƌŽůŽŐŝĐ sŝƌŽůŽŐŝĐ EŽsŝƌŽůŽŐŝĐ ĂƐĞůŝŶĞ,/sͲϭ ĂƐĞůŝŶĞϰн ƐǁŝƚĐŚĞĚƚŽd&ͬ&dͬd' ^ƵĐĐĞƐƐ EŽŶƌĞƐƉŽŶƐĞ ĂƚĂ ZE͕Đͬŵ> ĞůůŽƵŶƚ͕ĐĞůůƐͬŵŵϯ EŽƚƌĞĂƚŵĞŶƚͲĞŵĞƌŐĞŶƚ/E^d/ŽƌEZd/ŵƵƚĂƚŝŽŶƐŝŶƉĂƚŝĞŶƚƐǁŝƚŚs&ŝŶĞŝƚŚĞƌĂƌŵ;ϲ :ŽůLJs͘:͘ ŶƚŝŵŝĐƌŽďŝĂů ŚĞŵŽƚŚĞƌĂƉLJ͘EŽǀĞŵďĞƌ ϮϬϭϴ ĨĂŝůƵƌĞƐŝŶϮͲĚƌƵŐ͖ϰŝŶϯͲĚƌƵŐ͘ƌĞLJŽƵƌĞĂĚLJĂƚϰϴǁĞĞŬƐĚĂƚĂ͍ ĂŚŶW͕ĞƚĂů͘dŚĞ >ĂŶĐĞƚ͘EŽǀĞŵďĞƌ ϮϬϭϴ WƌĞĚŝĐƚŽƌƐŽĨǁŚŽ͞ĚŽĞƐŶŽƚĚŽǁĞůů͟ŽŶϮͲĚƌƵŐƚŚĞƌĂƉLJ͕ ^ƵŵŵĂƌLJ /ƚĂůŝĂŶĐŽŚŽƌƚ ĞƚǁĞĞŶŶĞǁĚƌƵŐƐŽĨĚŽƌĂǀŝƌŝŶĞ͕ďŝĐƚĞŐƌĂǀŝƌ͕ KĨϮϭϰϵƐǁŝƚĐŚĞƌƐŝŶ/ƚĂůŝĂŶĐŽŚŽƌƚ͕ŵĞĚŝĂŶĂŐĞϱϬ͕ ZsͬĐŽďŝͬd&ͬ&dǁŝƚŚǀĞƌLJƉŽƚĞŶƚĨŽƌŵĞƌĚƌƵŐƐ͕ ŵĞĚŝĂŶϰϱϳϳ͕ŵĞĚŝĂŶs>ϭ͘ϱϳůŽŐ;фϰϬĐŽƉŝĞƐͿ ϮϬϭϴŝƐĂŐŽŽĚLJĞĂƌ >ŽƚƐŽĨƉƌĞͲƚƌĞĂƚŵĞŶƚĞdžƉĞƌŝĞŶĐĞ;ϵϵ͘ϯйŚĂĚƚĂŬĞŶ /ďĂůŝnjƵŵĂď ĂŶĚĨŽƐƚĞŵƐĂǀŝƌ ƌĞƐĞƌǀĞĚĨŽƌǀĞƌLJ EZd/ŝŶƉĂƐƚ͖ϴϮ͘ϰйW/͖ϲϳ͘ϵйEEZd/͖ϯϮ͘Ϯй/E^d/Ϳ͘ ƌĞƐŝƐƚĂŶƚƉĂƚŝĞŶƚƐͲ ĨĞǁĞƌĂŶĚĨĞǁĞƌ KE>zWZ ͲƚƌĞĂƚŵĞŶƚǀŝƌĂůůŽĂĚƉƌĞĚŝĐƚĞĚǀŝƌŽůŽŐŝĐĨĂŝůƵƌĞŝŶ dǁŽĚƌƵŐƚŚĞƌĂƉLJ ŵƵůƚŝǀĂƌŝĂƚĞĂŶĂůLJƐŝƐ͘ EƚƌĞŶĚŽĨŚĂǀŝŶŐĂ'^^фϭ;ƉŽƐƐŝďůĞ ƌĞƐŝƐƚĂŶĐĞŝŶƚŚĞƉƌĞͲƐǁŝƚĐŚŐĞŶŽƚLJƉĞͿ tĞŽŶůLJŚĂǀĞƉŚĂƐĞϯĚĂƚĂŽŶd'ͬZWs;ƐǁŝƚĐŚͿ ĂŶĚd'ͬϯd;ŶĂŢǀĞͿ ŽƚƚŽŵůŝŶĞ͗ /ĨLJŽƵĂƌĞƌĞĂĚLJĨŽƌƚŚŝƐ͕ŽŶůLJĐŽŶƐŝĚĞƌƐǁŝƚĐŚŝŶŐŝĨ ƉĂƚŝĞŶƚϭͿƐƵƉƉƌĞƐƐĞĚ͖ϮͿĂĚŚĞƌĞŶƚďLJLJŽƵƌĞdžƉĞƌŝĞŶĐĞ͖ϯͿŚĂǀĞŶŽ WƌĞĚŝĐƚŽƌƐŽĨĚŽŝŶŐƉŽŽƌůLJŽŶƐǁŝƚĐŚĂƌĞŶŽƚ ŚŝƐƚŽƌLJŽĨŐĞŶŽƚLJƉŝĐƌĞƐŝƐƚĂŶĐĞƚŽĂŶLJĐŽŵƉŽŶĞŶƚŽĨLJŽƵƌϮͲĚƌƵŐ ǀŝƌŽůŽŐŝĐĂůůLJ ƐƵƉƉƌĞƐƐĞĚŽƌĂŶLJƌĞƐŝƐƚĂŶĐĞ ƌĞŐŝŵĞŶ͘ ƌĞLJŽƵƌĞĂĚLJ͍ ZŽƐƐĞƚƚŝ͘'ůĂƐŐŽǁ ,/sdŚĞƌĂƉLJ ĐŽŶĨĞƌĞŶĐĞ ϮϬϭϴ͘ďƐƚƌĂĐƚWϮϵϵ ϭϭ ϭϭͬϮϳͬϮϬϭϴ 7KDQN\RXWR'UV 'LDQH+DYOLU$QQLH /XHWNHPH\HU0HJ 1HZPDQDQG 'LYLVLRQRI+,9 ,QIHFWLRXV'LVHDVHV DQG*OREDO 0HGLFLQH ϭϮ Disclosures HIVmedicineintheeraof • Researchsupportfrom Karius immunemodulators PeterChinͲHongMD ProfessorofMedicine UCSF December2018 HIV-infected patients living longer Learningobjectives Afterattendingthispresentation,learnerswillbeableto: • Listthetypesofconditionsforwhichbiologicagentsmaybeprescribedfor peoplewithHIVinfection • Explainthemechanismofactioningeneraloftheseagentstoapatientin yourpracticesothatheorshemayunderstandwhycertainopportunistic infectionsandothercomplicationsmayarise • Describethearrayofinfectiousandothercomplicationsthatmayarise withtheseagents • Designstrategiesthatyoucanuseinclinictopreventinfectiousandother complications inyourpatients Slide 4 of 36 Lohse N et al, 2016, Ann Intern Med;165(10):749; ART cohort collab, 2017, Lancet ID, 4(8):e349 HIV-infected patients living longer Life expectancy in US declines for 2 years in row ÏAutoimmunity ÏMalignancy Slide 5 of 36 Lohse N et al, 2016, Ann Intern Med;165(10):749; ART cohort collab, 2017, Lancet ID, 4(8):e349 Slide 6 of 36 OEDC, CDC, The Economist Jan 4, 2018 Autoimmune disease and cancer increase with age Immunobiologics treat autoimmune disease and cancer TNF-Į inhibitors Infliximab Adalimumab Etanercept Rheumatoid arthritis Vasculitis Crohn disease Psoriasis Rheumatoid arthritis Vasculitis Crohn disease Psoriasis Ulcerative colitis Ulcerative colitis Anti-CD20 Rituximab Lymphoma Lymphoma Checkpoint block Ipilimumab CAR-T cells Melanoma Prostate cancer Lung cancer Leukemia Melanoma Prostate cancer Lung cancer Leukemia Slide 7 of 36 Slide 8 of 36 What is a “biologic”? Who is the most immune suppressed? ƒ Any biologically derived product ƒ Binds or interferes with a specific molecular target Monoclonal antibodies Receptor analogues Chimeric small molecules ƒ Abbreviations placed at the ends of the names of Heme malignancy/stem cell transplant therapeutic agents convey specific information relating to Organ transplant their structure: Autoimmune disease treatment Solid tumor treatment "-cept" refers to fusion of a receptor to the Fc part of human IgG1 HIV "-mab" indicates a monoclonal antibody (mAb) Congenital/acquired immune deficiency "-ximab" indicates a chimeric mAb Hyposplenism "-zumab" indicates a humanized mAb Slide 9 of 36 Slide 10 of 36 Type of immune defect related to drugs used How is this different from HIV immunosuppressed Humoral patients? immunity •Rituximab (anti-CD20) HIV Non-HIV •Hyposplenism •CVID (low IgG) Innate Immune Death of Cell- Heterogeneous mediated (PMNs) defect CD4+ T-cells immunity immunity • Solid organ transplant OI risk No reliable tests • Stem cell transplant • Cancer chemoRx CD4+ count • TNF-Į inhibitors • Chronic gran dz (CGD) stratification available •Steroids • Other biologics Slide 11 of 36 Slide 12 of 36 Case Case ƒ 56 year-old woman with HIV ƒ 56 year-old woman with HIV (CD4 360, VL <50) with Crohn (CD4 360, VL <50) with Crohn disease managed with disease managed with infliximab and 6-MP infliximab and 6-MP ƒ Presents to ED complaining of ƒ Presents to ED complaining of shortness of breath x 3 weeks shortness of breath x 3 weeks ƒ PPD negative prior. Lives in ƒ What else do you want to New York . Came back 4 weeks know? ago from a trip to Puerto Rico where she visited family and helped with property clean up Slide 13 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 14 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard 56 yo with Crohn disease on infliximab, short of breath Case ƒ 56 year-old woman with HIV What do you check next? (CD4 360, VL <50) with Crohn disease managed with A. Chest CT infliximab and 6-MP B. Interferon gamma release ƒ Presents to ED complaining of assay (IGRA) shortness of breath x 3 weeks C. Sputum AFB x 3 ƒ CXR shows patchy infiltrates D. Tuberculin Skin Test (TST) ƒ What do you check next? E. Repeat CXR Slide 15 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 16 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard MOA Case ƒ 56 year-old woman with HIV (CD4 360, VL <50) with Crohn disease managed with infliximab and 6-MP ƒ Presents to ED complaining of shortness of breath x 3 weeks ƒ Urinary histoplasma antigen positive. Chest CT: symmetric nodules Diagnosis: Acute histoplasmosis Slide 17 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 18 of 36 Scott DL et al, NEJM Aug 17, 2006 TNF-Į inhibitors: tuberculosis TNF-Į inhibitors: mycobacteria and fungi ƒ Post-marketing survey of TB cases following release ƒ Survey of serious infection on of infliximab (1998-2001) TNF-Į inhibitors in the US Ɠ Non-tuberculous mycobacteria: 32 ƒ 70 cases of TB Ɠ TB: 17 Ɠ Histoplasmosis: 56 ƒ Median time to diagnosis: 12 weeks (range 1-52) ƒ FDA alert 2008: 256 cases of ƒ TB characteristics histoplasmosis in patients on Ɠ Extrapulmonary disease: 57% TNF-Į inhibitors Ɠ Disseminated disease: 24% Endemic mycoses in the US Winthrop KL. CID. 2008 Slide 19 of 36 Keane J. NEJM. 2001 CXR showing disseminated TB in patient on infliximab Slide 20 of 36 Case Case ƒ 42 year-old male with Crohn ƒ 42 year-old male with Crohn disease x 3 years, started on disease x 3 years, started on infliximab after persistent infliximab after persistent diarrhea 5 months prior diarrhea 5 months prior ƒ Admitted with 3 weeks ƒ Admitted with 3 weeks shortness of breath, low grade shortness of breath, low grade temps, dry cough. No help with temps, dry cough. No help with amoxicillin x 1 week amoxicillin x 1 week ƒ What is your differential ƒ What diagnostic tests do you diagnosis? send? Slide 21 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong Slide 22 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong 42 y-o Crohn disease fevers, cough, short of breath Case What diagnostic tests do you send? ƒ Sputum AFB negative x 3 ƒ Sputum AFB Cx negative A. Chest CT ƒ Respiratory virus PCR negative B. Chest CT and Sputum AFB x 3 ƒ Chest CT: ground glass opacities and culture ƒ BAL DFA+ P. jiroveci C. Chest CT, Sputum AFB x 3 and ƒ HIV Ab positive culture and Respiratory virus panel ƒ Diagnosis: Pneumocystis pneumonia D. Chest CT, Sputum AFB x 3 and ƒ Treated with clindamycin and culture, Respiratory virus panel and primaquine (TMP/SMX allergic) Sputum DFA for PCP ƒ Started ART Case courtesy Dr. Ivan Hung, University of Hong Kong Slide 23 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong Slide 24 of 36 Biologics and PCP Case ƒ 74 year-old HIV-negative man ƒ Retrospective analysis of 2198 with interstitial lung disease and patients (across 8 studies) with chronic lymphocytic leukemia relapsed CLL or NHL on idelalisib ƒ Patients on idelalisib +/- co- ƒ Admitted with progressive therapy (ritux or ritux/benda) shortness of breath on exertion and dry cough for 1 month ƒ PCP RR: 12.5 ƒ Diagnosis: Pneumocystis ƒ Median time to PCP: 141 days pneumonia ƒ No standard PCP prophylaxis guidance Sehn LH, Blood, 2016 Furman, NEJM, 2014 Slide 25 of 36 Case courtesy Dr. Jen Mulliken, UCSF Slide 26 of 36 MOA Case ƒ 69 year-old HIV-negative woman with low grade lymphoma, treated only with rituximab (anti-CD20) ƒ Months after treatment, develops slowly progressive mental status changes ƒ CSF PCR positive for JC virus and MRI consistent with PML ƒ Diagnosis: Progressive Multifocal Leukoencephalopathy (PML) Slide 27 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Slide 28 of 36 Maloney DG, NEJM, May 24, 2012 Biologics and viral infections Cancer immunotherapy in the beginning ƒ Hepatitis B reactivation Reactivation with TNF-Į inhibitors reported Rituximab – common ƒ JC virus (progressive multifocal leukoencephalopathy) Natalizumab – must check JCV IgG Rituximab – reports, less common ƒ Varicella zoster virus Langer-Gould A. NEJM, 2005 Slide 29 of 36 Slide 30 of 36 Slide courtesy Dr. Gabe Mannis, UCSF How Jimmy Carter beat How Jimmy Carter beat cancer cancer TIME TIME January 20, 2017 January 20, 2017 New immunotherapy drug New immunotherapy drug behind Jimmy Carter’s behind Jimmy Carter’s cancer cure cancer cure The Guardian The Guardian December 6, 2015 December 6, 2015 Slide 31 of 36 Slide 32 of 36 Checkpoint blockade: a billion dollar industry ƒ Block the inhibitory receptor with monoclonal antibodies (CTLA-4, PD1) ƒ Target the immune system – not the cancer ƒ May lead to autoimmune disease & immune-related adverse events ƒ Infection risk may increase as immune suppression used to Skin and hair depigmentation after treating melanoma treat complications of therapy with anti-CTLA-4 Slide 33 of 36 Gandhi L et al, NEJM, April 16, 2018 Slide 34 of 36 Del Castillo M et al, CID, 2016 MOA Case ƒ 52 year-old male with HIV (CD4 450, VL <50 on abacavir/ dolutegravir/lamivudine) with skin squamous cell cancer. Enrolled in AMC-095 trial. On nivolumab x 1 year. Presents with fecal incontinence and diarrhea ƒ Diagnosis: Checkpoint inhibitor associated colitis ƒ Treated with prednisone high dose and infliximab. Nivolumab stopped ƒ Skin cancer in partial remission Severe colitis Slide 36 of 36 Slide 35 of 36 Postow MA et al, NEJM, Jan 11, 2018 Case courtesy Dr. Jackie Wang, UCSF “CAR” Adoptive T cell therapy: CAR T cells Gene therapy was a boy’s ƒ Chimeric Antigen Receptor last chance to stop (CAR) T cells are genetically modified T cells leukemia. And it worked. PBS ƒ T cells respond when tumor cell March 4, 2018 surface antigen recognized ƒ Substantial immune-related adverse events (cytokine release syndrome) ƒ Infection risk may increase as immune suppression used to treat complications of therapy Slide 37 of 36 Slide 38 of 36 Lee DW et al, Lancet, 2015 KQED, March 4, 2018 Evaluation prior to TNF-Į inhibitor use Evaluation prior to TNF-Į inhibitor use ƒ HIV ƒ HIV Is patient adequately immune reconstituted? CD4>200. Any drug Is patient adequately immune reconstituted? CD4>200. Any drug interactions? interactions? ƒ TB risk ƒ TB risk Check PPD or IGRA, CXR, take TB history Check PPD or IGRA, CXR, take TB history ƒ Endemic mycoses/fungi ƒ Endemic mycoses/fungi Take travel history, symptom check Take travel history, symptom check ƒ Hepatitis B ƒ Hepatitis B ƒ Vaccines ƒ Vaccines Check hepatitis B surface antigen and core antibody Check hepatitis B surface antigen and core antibody Slide 39 of 36 Slide 40 of 36 Anti-TNF inhibitors in patients with CD4<500 Slide 41 of 36 Slide 42 of 36 Fink DL et al, Int J STD&AIDS, 2017 Evaluation during biologic use Learningobjectives ƒ HIV Is patient maintaining good immune function? CD4? Afterattendingthispresentation,learnerswillbeableto: ƒ Infection vs “Infection” • Listthetypesofconditionsforwhichbiologicagentsmaybeprescribedfor Is patient experiencing any known adverse effect associated with the peoplewithHIVinfection biologic? • Explainthemechanismofactioningeneraloftheseagentstoapatientin yourpracticesothatheorshemayunderstandwhycertainopportunistic ƒ Vaccines infectionsandothercomplicationsmayarise Live vaccines usually contraindicated • Describethearrayofinfectiousandothercomplicationsthatmayarise withtheseagents ƒ Be vigilant • Designstrategiesthatyoucanuseinclinictopreventinfectiousandother Your patient may have a new complication not previously reported complications inyourpatients Slide 43 of 36 Thanks Michelle Hermiston, Ivan Hung, Camille Kotton, Jen Mulliken, Brian Schwartz, Paul Volberding, Jackie Wang &ODVVLFDQG&KDOOHQJLQJ&DVHVIURP +,9DVVRFLDWHG3XOPRQDU\'LVHDVH WKH+,9$,'6&OLQLFDQG%H\RQG 7KHVSHFWUXPRISXOPRQDU\GLVHDVHVLQ+,9LQIHFWHG /DXUHQFH+XDQJ0' 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/W͕KĐƚŽďĞƌϮϬϭϴ ZĞŵĞŵďĞƌƚŽƐĐƌĞĞŶ dƌŝƉůĞƚŚĞƌĂƉLJ ĂŶĚǀĂĐĐŝŶĂƚĞĨŽƌ E^ϱĂ E^ϱďEƵŬĞ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ ,sΘ,s ϵϱйĐƵƌĞƌĂƚĞĨŽƌŵŽƐƚƉĂƚŝĞŶƚƐ͕ƌĞŐĂƌĚůĞƐƐŽĨƌĞŐŝŵĞŶ ^ŝŵŝůĂƌƐŝĚĞĞĨĨĞĐƚƐ͗ŚĞĂĚĂĐŚĞ͕ŶĂƵƐĞĂ͕ĨĂƚŝŐƵĞ ,sƌƐĞŶĂůΘWƌŝŶĐŝƉĂůƐŽĨƚŚĞƌĂƉLJ ƵƌƌĞŶƚĐŽŵďŝŶĂƚŝŽŶƐ E^ϱĂďĂƐĞĚƚŚĞƌĂƉLJ E^ϱĂĂĐŬďŽŶĞ KŶĞĚƌƵŐĨƌŽŵϮŶĚ ĐůĂƐƐ E^ϱďEƵŬĞ E^ϱĂн^K& E^ϱĂ ;^ŽĨŽƐďƵǀŝƌͿ sĞůƉĂƚĂƐǀŝƌ н^K& ͞ ƉĐůƵƐĂ͟ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ WĂŶŐĞŶŽƚLJƉŝĐ >ĞĚŝƉĂƐǀŝƌ н^K& ͞,ĂƌǀŽŶŝ͟ 'ĞŶŽƚLJƉĞƐϭ͕ϰŽŶůLJ dƌŝƉůĞƚŚĞƌĂƉLJ E^ϱĂ E^ϱďEƵŬĞ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ ǁǁǁ͘ŚĐǀŐƵŝĚĞůŝŶĞƐ͘ŽƌŐ ϰ ϭϮͬϯͬϮϬϭϴ ƵƌƌĞŶƚĐŽŵďŝŶĂƚŝŽŶƐ E^ϱĂďĂƐĞĚƚŚĞƌĂƉLJ E^ϱĂĂĐŬďŽŶĞ KŶĞĚƌƵŐĨƌŽŵϮŶĚ ĐůĂƐƐ E^ϱďEƵŬĞ E^ϱĂнW/ ;^ŽĨŽƐďƵǀŝƌͿ E^ϱĂ WŝďƌĞŶƚĂƐǀŝƌ н ,sŝŶϮϬϭϴ 'ůĞĐĂƉƌĞǀŝƌ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ ͞DĂǀLJƌĞƚ͟ WĂŶŐĞŶŽƚLJƉŝĐ 'ƌĂnjŽƉƌĞǀŝƌ н ůďĂƐǀŝƌ ͞ĞƉĂƚŝĞƌ͟ dƌŝƉůĞƚŚĞƌĂƉLJ 'ĞŶŽƚLJƉĞƐϭ͕ϰ E^ϱĂ E^ϱďEƵŬĞ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ dƌĞĂƚŵĞŶƚƐĂǀĞƐůŝǀĞƐ ƵƌƌĞŶƚĐŽŵďŝŶĂƚŝŽŶƐ E^ϱĂďĂƐĞĚƚŚĞƌĂƉLJ E^ϱĂĂĐŬďŽŶĞ KŶĞĚƌƵŐĨƌŽŵϮŶĚ ĐůĂƐƐ E^ϱďEƵŬĞ E^ϱĂ ;^ŽĨŽƐďƵǀŝƌͿ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ E^ϱĂнE^ϱďнW/ ^ŽĨŽƐďƵǀŝƌ͕ sĞůƉĂƚĂǀŝƌ͕ sŽdžŝůĂƉƌĞǀŝƌ ;͞sŽƐĞǀŝ͟Ϳ dƌŝƉůĞƚŚĞƌĂƉLJ WĂŶŐĞŶŽƚLJƉŝĐ E^ϱĂ E^ϱďEƵŬĞ WƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ :ĂŶũƵĂ ^>ϮϬϭϴηϭϰϱ ϱ ϭϮͬϯͬϮϬϭϴ 'ƌĞĂƚŽƉƚŝŽŶƐĨŽƌƉƌĞǀŝŽƵƐůLJŚĂƌĚĞƌ ƌŽƉƉŝŶŐWƌŝĐĞƐ ƚƌĞĂƚƉŽƉƵůĂƚŝŽŶƐ ƌƵŐ tŚŽůĞƐĂůĞĂĐƋƵŝƐŝƚŝŽŶ ƉƌŝĐĞ ^K&ͬ>s džϭϮǁĞĞŬƐ ϵϰ͕ϱϬϬ ^K&ͬs >džϭϮǁĞĞŬƐ ϳϰ͕ϳϲϬ WĞŽƉůĞ ůŝǀŝŶŐǁŝƚŚ,/sΘ,s ƋƵŝǀĂůĞŶƚ ŽƵƚĐŽŵĞƐƚŽ,/sͲ ^K&ͬs > ͞ĂƵƚŚŽƌŝnjĞĚŐĞŶĞƌŝĐ͟ ĐŽŝŶĨĞĐƚŝŽŶ ƵŶŝŶĨĞĐƚĞĚΘĐŽŵƉĂƚŝďůĞǁŝƚŚZd Ϯϰ͕ϬϬϬ ZĞŶĂů&ĂŝůƵƌĞŝŶĐůƵĚŝŶŐ ^Z 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ ;ϮϬϭϵͿ ůďĂƐǀŝƌͬ'ƌĂnjŽƉƌĞǀŝƌ 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ džϴǁĞĞŬƐ Ϯϲ͕ϰϬϬ ŝƌƌŚŽƐŝƐŝŶĐůƵĚŝŶŐ ^K&ͬs > ĚĞĐŽŵƉĞŶƐĂƚĞĚĚŝƐĞĂƐĞ ^K&ͬ>s ůďĂƐǀŝƌͬ'ƌĂnjŽƉƌĞǀŝƌ džϭϮǁĞĞŬƐ Ϯϭ͕ϴϰϬ;ϲϬйƌĞĚƵĐƚŝŽŶͿ ;/ĨĚĞĐŽŵƉĞŶƐĂƚĞĚ͕ĂĚĚZsĂŶĚ ,/sͲ ĞƋƵŝǀĂůĞŶƚŽƵƚĐŽŵĞƐǁŝƚŚƚƌĞĂƚŝŶĐŽůůĂďŽƌĂƚŝŽŶǁŝƚŚůŝǀĞƌ ƚƌĂŶƐƉůĂŶƚƚĞĂŵŝĨĨĞĂƐŝďůĞͿ d< ,KD ^͗ ĐƚŝǀĞƐƵďƐƚĂŶĐĞ ƵƐĞĂŶĚͬŽƌ ĂƚĂ ƐƵƉƉŽƌƚĞdžĐĞůůĞŶƚŽƵƚĐŽŵĞƐ͕ ¾ džƉĞĐƚƉŽƚĞŶƚŝĂůĨŽƌŵƵůĂƌLJĐŚĂŶŐĞƐǁŝƚŚƉƌŝĐĞĚĞĐƌĞĂƐĞƐ ĂůĐŽŚŽůƵƐĞĚŝƐŽƌĚĞƌ ĂĚĚŝƚŝŽŶĂůƐƵƉƉŽƌƚŵĂLJďĞ ¾ WƌŝĐĞƐŚŽƵůĚEKdďĞƚŚĞŵĂũŽƌďĂƌƌŝĞƌƚŽ,sĐĂƌĞ ŶĞĐĞƐƐĂƌLJ &/ZK^/^ ĂůŝĨŽƌŶŝĂ,sWƌĞƐĐƌŝďŝŶŐůĂŶĚƐĐĂƉĞ Z ^dZ/d/KE^ ƐŽĨϳͬϭϴ͗DĞĚŝͲĐĂů ŶŽǁĂĚŚĞƌĞƐƚŽ^>ͬ/^ ŐƵŝĚĞůŝŶĞƐ͗dƌĞĂƚĂůůƌĞŐĂƌĚůĞƐƐŽĨĞdžƚĞŶƚŽĨ ĨŝďƌŽƐŝƐŝĨŶŽƚĚLJŝŶŐŽĨŶŽŶͲ,sĐĂƵƐĞ WƌĞĨĞƌƌĞĚ ^KZ/ dz ŽŶŵĂŶLJ Z ^dZ/d/KE^ DĞĚŝͲĐĂů ĨŽƌƵŵůĂƌŝĞƐ ůƚĞƌŶĂƚŝǀĞ ǁǁǁ͘ƐƚĂƚĞŽĨŚĞƉĐ͘ŽƌŐ ϲ ϭϮͬϯͬϮϬϭϴ 'ͬWŝŶƚĞƌĂĐƚŝŽŶƐǁŝƚŚZd ĂĐŬƚŽƚŚĞĂƐĞ ŽŵƉĂƚŝďůĞǁŝƚŚ/E^d/͕ ZŝůƉŝǀŝƌŝŶĞ͕EZd/^ ± 'ͬWŝŶĐƌĞĂƐĞƐ/ϳϰй͕ŶŽƚ ĐŽŶƐŝĚĞƌĞĚĐůŝŶŝĐĂůůLJ ƐŝŐŶŝĨŝĐĂŶƚ͕ĂƐƵƉƚŽϮ͘ϱdž ŝŶĐƌĞĂƐĞŝŶ/ƐŚŽǁŶƚŽďĞ ƵƌƌĞŶƚŝŶƐƵƌĂŶĐĞƉƌĞĨĞƌƐ'ͬWĨŽƌLJŽƵƌ ƐĂĨĞ ƉĂƚŝĞŶƚ͙͘ ĂƵƚŝŽŶǁŝƚŚ ůǀŝƚĞŐƌĂǀŝƌͬĐ EŽƚƌĞĐŽŵŵĞŶĚĞĚǁŝƚŚ W/ͬƌŽƌW/ͬĐĚƵĞƚŽůĂĐŬŽĨ ĐůŝŶŝĐĂůĚĂƚĂ ± EKdĐŽŵƉĂƚŝďůĞǁŝƚŚd ± ǀŽŝĚW/ͬƌн'ͬWŝŶĐŝƌƌŚŽƚŝĐƐ ŽŶŽƚ ŐŝǀĞǁŝƚŚ &sŽƌ ƚƌĂǀŝƌŝŶĞ ŚƚƚƉƐ͗ͬͬǁǁǁ͘ŚĐǀŐƵŝĚĞůŝŶĞƐ͘ŽƌŐͬƵŶŝƋƵĞͲƉŽƉƵůĂƚŝŽŶƐͬŚŝǀͲŚĐǀ 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ ;'ͬWͿ ĂĐŬƚŽŽƵƌƉĂƚŝĞŶƚ ͞DĂǀLJƌĞƚ͟ KŶ/ͬd&ͬ&dĂŶĚŽŵĞƉƌĂnjŽůĞ WĂŶŐĞŶŽƚLJƉŝĐ ;'dϭͲϲͿ ƵĞƚŽĨŽƌŵƵůĂƌLJƉƌĞĨĞƌĞŶĐĞĂŶĚĂĐŝĚƐƵƉƉƌĞƐƐŝŽŶ͕ ϯƉŝůůƐͬŽŶĐĞĚĂŝůLJ;ŶŽƚƐŵĂůů͊Ϳ 'ͬWdžϴǁĞĞŬƐƉƌĞƐĐƌŝďĞĚĨŽƌŶŽŶͲĐŝƌƌŚŽƚŝĐ ƚƌĞĂƚŵĞŶƚŶĂŢǀĞ ϴǁĞĞŬƐĨŽƌƚƌĞĂƚŵĞŶƚŶĂŢǀĞ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐƉĂƚŝĞŶƚƐ ŽŵƉůĞƚĞĚƚŚĞƌĂƉLJĂŶĚ,sZE;ͲͿϯŵŽŶƚŚƐĂĨƚĞƌ ;ŝŶĐůƵĚŝŶŐ,/sͿ ƐƚŽƉƉŝŶŐƚƌĞĂƚŵĞŶƚсhZ ĂŶďĞŐŝǀĞŶǁŝƚŚƌů фϯϬĂŶĚŝŶ ^Z /ŶƐƉŝƌĞĚďLJŚŝƐĐƵƌĞ͕ŚĞŚĂƐƐƚŽƉƉĞĚƵƐŝŶŐ/s ŽŵƉĂƚŝďůĞǁŝƚŚĂĐŝĚďůŽĐŬĞƌƐ ŵĞƚŚĂŵƉŚĞƚĂŵŝŶĞ͕ƐƚŝůůƐŵŽŬĞƐďƵƚĐƵƚƚŝŶŐĚŽǁŶ ƚŚŝƐĐƵƌĞǀŝƐŝƚ͕ƚĞƐƚƐ;нͿĨŽƌƐLJƉŚŝůŝƐĂŶĚ'͕ƌĂŝƐŝŶŐ ŽŶŽƚ ƵƐĞŝŶĚĞĐŽŵƉĞŶƐĂƚĞĚůŝǀĞƌĚŝƐĞĂƐĞ ĐŽŶĐĞƌŶĨŽƌŽŶŐŽŝŶŐƌŝƐŬƐĨŽƌƐĞdžƵĂů,sĂĐƋƵŝƐŝƚŝŽŶ ;;ŚŝůĚͲWƵŐŚůĂƐƐŽƌͿ ϳ ϭϮͬϯͬϮϬϭϴ Z^ηϮtŚŝĐŚŝƐƚƌƵĞĂďŽƵƚƚŚĞƌŝƐŬŽĨ Z^ηϮtŚŝĐŚŝƐƚƌƵĞĂďŽƵƚƚŚĞƌŝƐŬŽĨ ƐĞdžƵĂůůLJĂĐƋƵŝƌĞĚ,sŝŶD^D͍ ƐĞdžƵĂůůLJĂĐƋƵŝƌĞĚ,sŝŶD^D͍ ϭͿ h^ƌĂƚĞƐŽĨ,sƌĞŝŶĨĞĐƚŝŽŶD^DĂƌĞƐŝŵŝůĂƌƚŽ ϭͿ h^ƌĂƚĞƐŽĨ,sƌĞŝŶĨĞĐƚŝŽŶD^DĂƌĞEKd ƌĂƚĞƐŝŶ ƵƌŽƉĞ ƐŝŵŝůĂƌƚŽƌĂƚĞƐŝŶ ƵƌŽƉĞ;ƐŽĨĂƌͿ ϮͿ ^ĞdžƵĂůŝŶĨĞĐƚŝŽŶŚĂƐŽŶůLJďĞĞŶĚĞƐĐƌŝďĞĚŝŶ D^DůŝǀŝŶŐǁŝƚŚ,/s͕ŶŽƚŝŶ,/s;ͲͿD^D ϯͿ ZĞŝŶĨĞĐƚŝŽŶƌĂƚĞƐŝŶ,/s;нͿD^DŝŶ ƵƌŽƉĞ ŚĂǀĞďĞĞŶƌĞƉŽƌƚĞĚĂƐŚŝŐŚĂƐϭϬйƉĞƌLJĞĂƌ ϰͿ WŽƐƚͲĞdžƉŽƐƵƌĞƉƌŽƉŚLJůĂdžŝƐĨŽƌ,sǁŝƚŚƐ ŝƐƌĞĐŽŵŵĞŶĚĞĚĨŽƌŚŝŐŚƌŝƐŬĞdžƉŽƐƵƌĞ;ƐĞdžƵĂů ŽƌƉĂƌĞŶƚĞƌĂůͿ ŚĂŝůůŽŶ ^>ϮϬϭϳ Z^ηϮtŚŝĐŚŝƐƚƌƵĞĂďŽƵƚƚŚĞƌŝƐŬŽĨ Z^ηϮtŚŝĐŚŝƐƚƌƵĞĂďŽƵƚƚŚĞƌŝƐŬŽĨ ƐĞdžƵĂůůLJĂĐƋƵŝƌĞĚ,sŝŶD^D͍ ƐĞdžƵĂůůLJĂĐƋƵŝƌĞĚ,sŝŶD^D͍ ϭͿ h^ƌĂƚĞƐŽĨ,sƌĞŝŶĨĞĐƚŝŽŶD^DĂƌĞƐŝŵŝůĂƌƚŽ ϭͿ h^ƌĂƚĞƐŽĨ,sƌĞŝŶĨĞĐƚŝŽŶD^DĂƌĞƐŝŵŝůĂƌƚŽ ƌĂƚĞƐŝŶ ƵƌŽƉĞ ƌĂƚĞƐŝŶ ƵƌŽƉĞ ϮͿ ^ĞdžƵĂůŝŶĨĞĐƚŝŽŶŚĂƐŽŶůLJďĞĞŶĚĞƐĐƌŝďĞĚŝŶ ϮͿ ^ĞdžƵĂůŝŶĨĞĐƚŝŽŶŚĂƐŽŶůLJďĞĞŶĚĞƐĐƌŝďĞĚŝŶ D^DůŝǀŝŶŐǁŝƚŚ,/s͕ŶŽƚŝŶ,/s;ͲͿD^D D^DůŝǀŝŶŐǁŝƚŚ,/s͕ŶŽƚŝŶ,/s;ͲͿD^D ϯͿ ZĞŝŶĨĞĐƚŝŽŶƌĂƚĞƐŝŶD^DŝŶ ƵƌŽƉĞŚĂǀĞ ƋƵĂůƌŝƐŬŽĨ,sŝŶ&ƌĞŶĐŚ <ĂŝƐĞƌWƌ W ĐŽŚŽƌƚ͗Ϯн ,/sнD^DǀƐ,/s;ͲͿŽŶWƌ W ŝŶĐŝĚĞŶƚ,sŝŶĨĞĐƚŝŽŶƐ ďĞĞŶƌĞƉŽƌƚĞĚĂƐŚŝŐŚĂƐϭϬйƉĞƌLJĞĂƌ;ϴϯй ,/sнͿ /ŶŐůŝƚnj ZK/ϮϬϭϴ ŽƚƚĞ ZK/ϮϬϭϴ sŽůŬ͕,ĂƌĞ/ϮϬϭϲ ϴ ϭϮͬϯͬϮϬϭϴ Z^ηϮtŚŝĐŚŝƐƚƌƵĞĂďŽƵƚƚŚĞƌŝƐŬŽĨ ĂƐĞηϮ ƐĞdžƵĂůůLJĂĐƋƵŝƌĞĚ,sŝŶD^D͍ ϱϴLJĞĂƌŽůĚǁŽŵĂŶ͕,/sǁĞůůĐŽŶƚƌŽůůĞĚŽŶ ϭͿ h^ƌĂƚĞƐŽĨ,sƌĞŝŶĨĞĐƚŝŽŶD^DĂƌĞƐŝŵŝůĂƌƚŽ ĂƌƵŶĂǀŝƌͬƌ͕d'͕&dͬd&͕ŚŝƐƚŽƌLJŽĨƉƌŝŽƌ,/s ĚƌƵŐƌĞƐŝƐƚĂŶĐĞ͘ ƌĂƚĞƐŝŶ ƵƌŽƉĞ ŚƌŽŶŝĐ,s͕ŐĞŶŽƚLJƉĞϭď͕ŝŶĨĞĐƚĞĚǀŝĂƌĞŵŽƚĞ ϮͿ ^ĞdžƵĂůŝŶĨĞĐƚŝŽŶŚĂƐŽŶůLJďĞĞŶĚĞƐĐƌŝďĞĚŝŶ /h͕ŶŽƵƐĞdžLJĞĂƌƐ͘ D^DůŝǀŝŶŐǁŝƚŚ,/s͕ŶŽƚŝŶ,/s;ͲͿD^D ZĞƉŽƌƚƐĚĂŝůLJĂůĐŽŚŽůƵƐĞΘƵůƚƌĂƐŽƵŶĚŝƐ ĐŽŶƐŝƐƚĞŶƚǁŝƚŚĐŝƌƌŚŽƐŝƐ͘,ĂƐŶŽŚŝƐƚŽƌLJŽĨ ϯͿ ZĞŝŶĨĞĐƚŝŽŶƌĂƚĞƐŝŶ,/s;нͿD^DŝŶ ƵƌŽƉĞ ŚĞƉĂƚŝĐĚĞĐŽŵƉĞŶƐĂƚŝŽŶ;ǀĂƌŝĐĞƐ͕ĂƐĐŝƚĞƐ͕ ŚĂǀĞďĞĞŶƌĞƉŽƌƚĞĚĂƚϭϬйƉĞƌLJĞĂƌ ĞŶĐĞƉŚĂůŽƉĂƚŚLJͿĂŶĚŝƐĐƵƌƌĞŶƚŚŝůĚͲWƵŐŚ ;dWͲͿ ϰͿ WŽƐƚͲĞdžƉŽƐƵƌĞƉƌŽƉŚLJůĂdžŝƐ;W WͿĨŽƌ,sǁŝƚŚ ^ŚĞŝƐƌĞĂĚLJƚŽƚƌĞĂƚŚĞƌ,s ďƵƚŶŽƚLJĞƚƚŽĐƵƚ ƐŝƐEKdƌĞĐŽŵŵĞŶĚĞĚĨŽƌŚŝŐŚƌŝƐŬ ďĂĐŬŽŶŚĞƌĂůĐŽŚŽů ĞdžƉŽƐƵƌĞ;ƐĞdžƵĂůŽƌƉĂƌĞŶƚĞƌĂůͿ EĂŐŐŝĞ /ϮϬϭϳ Z^ηϯtŚĂƚZdƌĞƋƵŝƌĞƐĚŽƐĞ ĂĐŬƚŽLJŽƵƌƉĂƚŝĞŶƚ ĂĚũƵƐƚŵĞŶƚŝŶdWͲĐŝƌƌŚŽƐŝƐ͍ ϭͿ ZŝƚŽŶĂǀŝƌƐƚĞĚĚĂƌƵŶĂǀŝƌ 'ŝǀĞŶŽŶŐŽŝŶŐƌŝƐŬĨŽƌ,sĂĐƋƵŝƐŝƚŝŽŶ ϮͿ dĞŶŽĨŽǀŝƌ ĂůĂĨĞŶĂŵŝĚĞ ;d&Ϳ ƚŚƌŽƵŐŚD^DƐĞdžƵĂůĐŽŶƚĂĐƚ͕LJŽƵĐŽŶƚŝŶƵĞƚŽ ƐĐƌĞĞŶŚŝŵǁŝƚŚ,sZEĞǀĞƌLJϲͲϭϮŵŽŶƚŚƐ ϯͿ ďĂĐĂǀŝƌ ϰͿ ŽůƵƚĞŐƌĂǀŝƌ ϱͿ ZŝůƉǀŝƌŝŶĞ ϵ ϭϮͬϯͬϮϬϭϴ Z^ηϯtŚĂƚZdƌĞƋƵŝƌĞƐĚŽƐĞ dKŚ ĂŶĚ,s ĂĚũƵƐƚŵĞŶƚŝŶdWͲĐŝƌƌŚŽƐŝƐ͍ ůĐŽŚŽůŝŶĐƌĞĂƐĞƐƌŝƐŬŽĨĨŝďƌŽƐŝƐƉƌŽŐƌĞƐƐŝŽŶĂŶĚ ,ŝŶƚŚŽƐĞǁŝƚŚ,sŝŶĨĞĐƚŝŽŶ ϭͿ ZŝƚŽŶĂǀŝƌƐƚĞĚĚĂƌƵŶĂǀŝƌ ,ŝŐŚĞƌ>d&hĂŶĚƉƌĞŵĂƚƵƌĞĚŝƐĐŽŶƚŝŶƵĂƚŝŽŶ ϮͿ dĞŶŽĨŽǀŝƌ ĂůĂĨĞŶĂŵŝĚĞ ;d&Ϳ 'ĞŶĞƌĂůůLJƐŝŵŝůĂƌ^sZƌĂƚĞƐ ϯͿ ďĂĐĂǀŝƌ͗ĞĐƌĞĂƐĞ ƚŽϮϬϬŵŐ/ŝĨdWͲ ϰͿ ŽůƵƚĞŐƌĂǀŝƌ ϱͿ ZŝůƉǀŝƌŝŶĞ DŽƐƚ͛ƐĐŽŵƉĂƚŝďůĞǁŝƚŚŶĂůƚƌĞdžŽŶĞ ŚƌŝƐƚĞŶƐĞŶϮϬϭϴ/^,^h Z^ηϯtŚĂƚZdƌĞƋƵŝƌĞƐĚŽƐĞ ĂĚũƵƐƚŵĞŶƚŝŶdWͲĐŝƌƌŚŽƐŝƐ͍ ϭͿ ZŝƚŽŶĂǀŝƌƐƚĞĚĚĂƌƵŶĂǀŝƌ ϮͿ dĞŶŽĨŽǀŝƌ ĂůĂĨĞŶĂŵŝĚĞ ;d&Ϳ ϯͿ ďĂĐĂǀŝƌ͗ ĞĐƌĞĂƐĞ ƚŽϮϬϬŵŐ/ŝĨdWͲ Ύ ϰͿ ŽůƵƚĞŐƌĂǀŝƌ ϱͿ ZŝůƉǀŝƌŝŶĞ sK/ŝŶĚĞĐŽŵƉĞŶƐĂƚĞĚĚŝƐĞĂƐĞ;dWͲŽƌdWͲͿ ϭϬ ϭϮͬϯͬϮϬϭϴ 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ϭϮǁĞĞŬƐĂĨƚĞƌƚƌĞĂƚŵĞŶƚсƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ ƵƉƐďƵƚĨŝŶŝƐŚĞƐϭϮǁĞĞŬƐŽĨƚŚĞƌĂƉLJŽǀĞƌĂϭϰ 'dϯ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐ͕ŶŽƌŵĂůƌĞŶĂůĨƵŶĐƚŝŽŶ ǁĞĞŬƐƉĂŶ WD,͗,dEĂŶĚ' Z ,sZEϭϮǁĞĞŬƐĂĨƚĞƌĨŝŶŝƐŚŝŶŐƚŚĞƌĂƉLJŝƐ KŶďĞŶĂnjĞƉƌŝůĂŶĚŽŵĞƉƌĂnjŽůĞ ƵŶĚĞƚĞĐƚĂďůĞсhZ ͊ ZĞĂĚLJƚŽďĞƌĞƚƌĞĂƚĞĚͲ ͞ƵƚŽŶůLJŝĨLJŽƵĂƌĞƐƵƌĞ LJŽƵĐĂŶŐĞƚŵĞĐƵƌĞĚ͊͟ ĨƚĞƌƚŚĞĐƵƌĞ͗,ƐĐƌĞĞŶŝŶŐ Z^ηϰ͗tŚĂƚĚŽĞƐƚŚŝƐƉĂƚŝĞŶƚŶĞĞĚ /Ĩ&ϯͬ&ϰ;ŽŶƐĐĂůĞŽĨ&ϬͲ&ϰͿĂƚƚŝŵĞŽĨƚƌĞĂƚŵĞŶƚ͕ĐŽŶƚŝŶƵĞ ƚŽƐĐƌĞĞŶĨŽƌŚĞƉĂƚŽĐĞůůƵůĂƌĐĂƌĐŝŶŽŵĂǁŝƚŚƋϲŵŽŶƚŚƐ ďĞĨŽƌĞ,sƌĞƚƌĞĂƚŵĞŶƚ͍ ŝŵĂŐŝŶŐ͕ĞǀĞŶŝĨĨŝďƌŽƐŝƐƌĞŐƌĞƐƐĞƐ ϭͿ ,sƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐ EKŝƌƌŚŽƐŝƐ t/d,^sZ ϮͿ ƚŽĞŶƐƵƌĞŶŽƚĂŶĞŵŝĐĂƐǁŝůůůŝŬĞůLJƌĞĐĞŝǀĞ ƌŝďĂǀŝƌŝŶ ŝƌƌŚŽƐŝƐ t/d,^sZ ϯͿ ŚĂŶŐĞŝŶ,/sŵĞĚŝĐĂƚŝŽŶ ϰͿ ZĞĚƵĐĞͬƐƚŽƉWW/ ŝƌƌŚŽƐŝƐt/d, EK^sZ ϱͿ ĞŵŽŶƐƚƌĂƚŝŽŶŽĨ&ϰĨŝďƌŽƐŝƐŽƌĂƐŝŐŶŝĨŝĐĂŶƚĐŽͲ ŵŽƌďŝĚŝƚLJƚŽŐĞƚƌĞƉĞĂƚƚƌĞĂƚŵĞŶƚĂƉƉƌŽǀĞĚ dŚŝƐ͞ŽŶĞƐŝnjĞĨŝƚƐĂůůĂƉƉƌŽĂĐŚ͟ǁŝůůŽǀĞƌƐĐƌĞĞŶ ƐŽŵĞǁŝƚŚ &ϯͬ&ϰƐĂŶĚƵŶĚĞƌƐĐƌĞĞŶ ƐŽŵĞĂƚƌŝƐŬǁͬŽĨŝďƌŽƐŝƐ ŽŶƐŝĚĞƌƵƐŝŶŐ,ƌŝƐŬĞƐƚŝŵĂƚŽƌ͗ǁǁǁ͘ŚĐĐƌŝƐŬ͘ĐŽŵ /ŽĂŶŶŽƵ ϮϬϭϴ:,ĞƉ ϭϮ ϭϮͬϯͬϮϬϭϴ Z^͗tŚĂƚĚŽĞƐƚŚŝƐƉĂƚŝĞŶƚŶĞĞĚ dƌĞĂƚŵĞŶƚĂĨƚĞƌĨĂŝůƵƌĞ ďĞĨŽƌĞ,sƌĞƚƌĞĂƚŵĞŶƚ͍ ' EKdzW ϯ ϭͿ ,sƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐ ϮͿ ƚŽĞŶƐƵƌĞŶŽƚĂŶĞŵŝĐĂƐǁŝůůůŝŬĞůLJƌĞĐĞŝǀĞ ƌŝďĂǀŝƌŝŶ ϯͿ ŚĂŶŐĞŝŶ,/sŵĞĚŝĐĂƚŝŽŶ ' EKdzW ϭ ϰͿ ZĞĚƵĐĞͬƐƚŽƉWW/Ͳ ĚƵĞƚŽĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶ ϱͿ ĞŵŽŶƐƚƌĂƚŝŽŶŽĨ&ϰĨŝďƌŽƐŝƐŽƌĂƐŝŐŶŝĨŝĐĂŶƚĐŽͲ ŵŽƌďŝĚŝƚLJƚŽŐĞƚƌĞƉĞĂƚƚƌĞĂƚŵĞŶƚĂƉƉƌŽǀĞĚ ϲϬLJ͘Ž͘ ŵĂŶ͕,/sǁĞůůĐŽŶƚƌŽůůĞĚŽŶZsͬĐͬ&dͬd&͕,s 'dϯ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐ͕ƉƌŝŽƌ,sƚƌĞĂƚŵĞŶƚƵŶƐƵĐĐĞƐƐĨƵůǁŝƚŚ ϭϮǁĞĞŬƐŽĨ^K&ͬ>s Z^͗tŚĂƚĚŽĞƐƚŚŝƐƉĂƚŝĞŶƚŶĞĞĚ ^K&ͬs >ͬsKy ďĞĨŽƌĞ,sƌĞƚƌĞĂƚŵĞŶƚ͍ ͞sŽƐĞǀŝ͟ ϭͿ ,sƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐ ϭϮǁĞĞŬƐ͕ŽŶĞƉŝůůĚĂŝůLJ͕ ƉĂŶŐĞŶŽƚLJƉŝĐ͕ŚŝŐŚĐƵƌĞƌĂƚĞƐ ϮͿ ƚŽĞŶƐƵƌĞŶŽƚĂŶĞŵŝĐĂƐǁŝůůůŝŬĞůLJƌĞĐĞŝǀĞ EK,sƌƵŐƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐ ƌŝďĂǀŝƌŝŶ ŶĞĐĞƐƐĂƌLJ EŽƚƌĞĐŽŵŵĞŶĚĞĚĨŽƌƌů ф ϯͿ ŚĂŶŐĞŝŶ,/sŵĞĚŝĐĂƚŝŽŶ ϯϬ ϰͿ ZĞĚƵĐĞͬƐƚŽƉWW/ ĂŶŶŽƚďĞƵƐĞĚŝŶ ĚĞĐŽŵƉĞŶƐĂƚĞĚůŝǀĞƌĚŝƐĞĂƐĞ ϱͿ ĞŵŽŶƐƚƌĂƚŝŽŶŽĨ&ϰĨŝďƌŽƐŝƐŽƌĂƐŝŐŶŝĨŝĐĂŶƚĐŽͲ ĚƵĞ,sW/ ^ĂŵĞĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐĂƐ ŵŽƌďŝĚŝƚLJƚŽŐĞƚƌĞƉĞĂƚƚƌĞĂƚŵĞŶƚĂƉƉƌŽǀĞĚ ^K&ͬs >ďƵƚĂĚĚĞĚŝŶƚĞƌĂĐƚŝŽŶƐ ϲϬLJ͘Ž͘ ŵĂŶ͕,/sǁĞůůĐŽŶƚƌŽůůĞĚŽŶZsͬĐͬ&dͬd&͕,s ĚƵĞƚŽ,sW/ĐŽŵƉŽŶĞŶƚ 'dϯ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐ͕ƉƌŝŽƌ,sƚƌĞĂƚŵĞŶƚƵŶƐƵĐĐĞƐƐĨƵůǁŝƚŚ ± ǀŽŝĚWW/͕ĂĐŝĚďůŽĐŬĞƌƐ ϭϮǁĞĞŬƐŽĨ^K&ͬ>s ŽŵƉĂƚŝďůĞǁŝƚŚZsͬƌͬĐ ϭϯ ϭϮͬϯͬϮϬϭϴ hŶŵĞƚEĞĞĚƐ WƌĞŐŶĂŶƚǁŽŵĞŶ ± WƌĞǀĂůĞŶĐĞĂƐŚŝŐŚĂƐϰйŝŶƐŽŵĞh^ĐŽŚŽƌƚƐ ± EŽ&ĂƉƉƌŽǀĞĚƚƌĞĂƚŵĞŶƚŝŶƉƌĞŐŶĂŶĐLJ ± ZŝƐŬŽĨŵĂƚĞƌŶĂůͲĐŚŝůĚƚƌĂŶƐŵŝƐƐŝŽŶΕϱй͕ŚŝŐŚĞƌŝŶ,/s;нͿ ǁŽŵĞŶ;ƵƉƚŽϭϬͲϮϬйͿ tŚĂƚ͛ƐŽŶƚŚĞ,s,ŽƌŝnjŽŶ͍ ± W<ĚĂƚĂĨŽƌƚŚĐŽŵŝŶŐŽŶ^K&ͬ>sŝŶƉƌĞŐŶĂŶĐLJ;EdϬϮϲϴϯϬϬϱͿ ŚŝůĚƌĞŶ ± dĞƐƚĂƚϮͲϲŵŽŶƚŚƐŽĨĂŐĞĂŶĚĂŐĂŝŶĂƚϭϴŵŽŶƚŚƐ ± >ŝŵŝƚĞĚĨŝďƌŽƐŝƐƉƌŽŐƌĞƐƐŝŽŶĚƵƌŝŶŐĐŚŝůĚŚŽŽĚ ± KƌĂůƐŽŶůLJĂƉƉƌŽǀĞĚĨŽƌшϭϮLJĞĂƌƐŽůĚ͕ĞŵĞƌŐŝŶŐW< ĚĂƚĂĨŽƌϯͲϭϮLJƌƐ ŽůĚ dŚŽƐĞǁŚŽĐĂŶ͛ƚĐŽŵƉůĞƚĞϴͲϭϮǁĞĞŬƐŽĨŽƌĂů ŵĞĚŝĐĂƚŝŽŶƐ ± >ŽŶŐĂĐƚŝŶŐ,sŝŶũĞĐƚĂďůĞ͙͍ ,sƉƌĞǀĞŶƚĂƚŝǀĞǀĂĐĐŝŶĞͲ ƐƚĂLJƚƵŶĞĚ͊ EŽŶĞǁ,sĚƌƵŐƐ ǁǁǁ͘ ŶĚ,ĞƉ^&͘ŽƌŐ ϭϰ ϭϮͬϯͬϮϬϭϴ ^ƵŵŵĂƌLJ ϴͲϭϮǁĞĞŬƐŽĨǁĞůůƚŽůĞƌĂƚĞĚƚŚĞƌĂƉLJ ĐŽŵƉĂƚŝďůĞǁŝƚŚZdƉƌŽǀŝĚĞƐĐƵƌĂƚŝǀĞ ƚŚĞƌĂƉLJĨŽƌĂůŵŽƐƚĂůůůŝǀŝŶŐǁŝƚŚ,s dƌĞĂƚŝŶŐƐĂǀĞƐůŝǀĞƐĂŶĚŝƐĐŽƐƚĞĨĨĞĐƚŝǀĞ ,/sƉƌŽǀŝĚĞƌƐĂƌĞŽŶƚŚĞĨƌŽŶƚůŝŶĞƐŽĨ,s ĞůŝŵŝŶĂƚŝŽŶͲ ƚĞƐƚĂŶĚŵĂŬĞĂƉůĂŶǁŝƚŚĂůů LJŽƵƌƉĂƚŝĞŶƚƐ͊ ƵƌŝŶŐƉĂƚŝĞŶƚƐŝƐǀĞƌLJĂĐŚŝĞ dŚĂŶŬLJŽƵ͊ ϭϱ ϭϮͬϰͬϮϬϭϴ YƵĞƐƚŝŽŶƚŽƉĂŶĞů ,ŽǁĚŽLJŽƵŚĂŶĚůĞŵŝƐƐĞĚĚŽƐĞƐŽĨ,s ŵĞĚŝĐĂƚŝŽŶƐ͍ ,ĞƉĂƚŝƚŝƐWĂŶĞů ,ŽǁůŽŶŐŝƐdKKůŽŶŐƚŽƌĞƐƚĂƌƚĂĨƚĞƌĂŶ ŝŶƚĞƌƌƵƉƚŝŽŶ͍ DD,ϮϬϭϴ E,KZ͗,ŝŐŚ^sZĚĞƐƉŝƚĞŝŵƉĞƌĨĞĐƚ YƵĞƐƚŝŽŶηϭ ĂĚŚĞƌĞŶĐĞ zŽƵƌ,s'dϭĂƉĂƚŝĞŶƚŝƐďĞŝŶŐƚƌĞĂƚĞĚǁŝƚŚ ƐŽĨŽƐďƵǀŝƌͬǀĞůƉĂƚĂƐǀŝƌ͘^ŚĞŝƐŚĞƌĞĨŽƌǁĞĞŬϲŵĞĚŝĐĂƚŝŽŶ ƉŝĐŬƵƉ͕ďƵƚƐƚŝůůŚĂƐĂƉƉƌŽdžŝŵĂƚĞůLJϴĚĂLJƐŽĨŵĞĚŝĐĂƚŝŽŶƐ &ŝŶŝƐŚŝŶŐшϭϰ ĚĂLJƐůĂƚĞĚŝĚŶŽƚ ƐŚĞŚĂƐŶ͛ƚƚĂŬĞŶ͘^ŚĞƌĞƉŽƌƚƐŵŝƐƐŝŶŐΕϭƉŝůůͬǁĞĞŬ͘tĞĞŬ ƐŝŐŶŝĨŝĐĂŶƚůLJ ϰ,sZEсϱϳ/hͬŵů ŝŵƉĂĐƚ^sZ tŚĂƚĚŽLJŽƵĚŽ͍ ϭͿ ^ƚŽƉ,sƚƌĞĂƚŵĞŶƚŐŝǀĞŶƵŶĂĐĐĞƉƚĂďůLJŚŝŐŚƌŝƐŬŽĨ ,sƌĞƐŝƐƚĂŶĐĞ ϮͿ ŚĞĐŬ,sZEʹ ŝĨŶŽƚƐƵƉƉƌĞƐƐĞĚ͕ƚŚĞŶƐƚŽƉ,s ƚƌĞĂƚŵĞŶƚ ϯͿ /ŶƐƚƌƵĐƚŚĞƌƚŽĐŽŶƚŝŶƵĞƚĂŬŝŶŐŵĞĚŝĐĂƚŝŽŶƐĚĂŝůLJ͕ ƐƚŽƉƉŝŶŐǁŚĞŶĂůůŵĞĚƐĂƌĞĐŽŵƉůĞƚĞĚ;ϭϮǁĞĞŬƐ ƚĂŬĞŶŽǀĞƌϭϯͲϭϰǁĞĞŬƐͿ ϰͿ WƌŽǀŝĚĞĂŶĂĚĚŝƚŝŽŶĂůĞdžƚƌĂϰǁĞĞŬƐŽĨ^K&ͬs >;ϭϲ ǁĞĞŬƐƚŽƚĂůͿ <ĂƚƚĂŬƵnjŚLJ ^>ϮϬϭϴ ϭ ϭϮͬϰͬϮϬϭϴ ,sWƌŽƚĞĂƐĞ/ŶŚŝďŝƚŽƌƐŝŶĐŝƌƌŚŽƐŝƐ ,ŝŐŚĞƌĚƌƵŐĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨW/͛ƐŝŶ ĚĞĐŽŵƉĞŶƐĂƚĞĚĐŝƌƌŚŽƐŝƐ EŽĚĂƚĂǁŝƚŚŵŽƐƚW/͛ƐĨŽƌƵƐĞŝŶ ĚĞĐŽŵƉĞŶƐĂƚĞĚĐŝƌƌŚŽƐŝƐ ŽŶĐĞƌŶĨŽƌĞdžĂĐĞƌďĂƚŝŽŶŽĨůŝǀĞƌĚLJƐĨƵŶĐƚŝŽŶ ǁŝƚŚƐŽŵĞŽĨ,sW/͛Ɛ Z D/E Z ŚŝůĚͲWƵŐŚůĂƐƐŝĨŝĐĂƚŝŽŶŽĨĐŝƌƌŚŽƐŝƐƐĞǀĞƌŝƚLJ ŽŵƉŽŶĞŶƚƐ͗ƐĐŝƚĞƐ͕ŝůŝƌƵďŝŶ͕ůďƵŵŝŶ͕/EZ͕ ŶĐĞƉŚĂůŽƉĂƚŚLJͲ ƉůƵŐŝŶƚŽĂŶLJŽŶͲůŝŶĞĐĂůĐƵůĂƚŽƌ Wd͗ϱͲϲ;ĐŽŵƉĞŶƐĂƚĞĚͿ Wd͗ϳͲϵ Wd͗ϭϬͲϭϱ <ĂƚƚĂŬƵnjŚLJ ^>ϮϬϭϴ YƵĞƐƚŝŽŶηϮ ϱϲLJĞĂƌŽůĚŵĂŶ͕ŬŶŽǁŶĐŝƌƌŚŽƐŝƐ͕ŚĞƌĞĨŽƌƌĞƚƌĞĂƚŵĞŶƚ YƵĞƐƚŝŽŶƚŽƚŚĞƉĂŶĞůŝƐƚ ĨŽƌ,s'dϭĂŝŶĨĞĐƚŝŽŶ͕ĂĨƚĞƌĨĂŝůŝŶŐƚŽďĞĐƵƌĞĚǁŝƚŚϭϮ ǁĞĞŬƐŽĨ^K&ͬs >ϵŵŽŶƚŚĂŐŽ͘,ĞŚĂƐĂŚŝƐƚŽƌLJŽĨϭ ĞƉŝƐŽĚĞŽĨĂƐĐŝƚĞƐϮLJĞĂƌƐĂŐŽŝŶƚŚĞƐĞƚƚŝŶŐŽĨŚĞĂǀLJ tŚĂƚŝƐƚŚĞĐŽŶĐĞƌŶǁŝƚŚ,sƉƌŽƚĞĂƐĞ ĚƌŝŶŬŝŶŐ͘,ĞŝƐŶŽǁĂďƐƚŝŶĞŶƚĨƌŽŵĂůĐŽŚŽůĂŶĚŚĂƐŚĂĚ ŝŶŚŝďŝƚŽƌƐŝŶĚĞĐŽŵƉĞŶƐĂƚĞĚĚŝƐĞĂƐĞ͍ ŶŽĨƵƌƚŚĞƌĞƉŝƐŽĚĞƐŽĨŚĞƉĂƚŝĐĚĞĐŽŵƉĞŶƐĂƚŝŽŶ͘zŽƵ ǁŽƵůĚůŝŬĞƚŽƚƌĞĂƚŚŝŵǁŝƚŚ^K&ͬs >ͬsKyďƵƚĂƌĞ ,ŽǁĚŽLJŽƵƚŚŝŶŬĂďŽƵƚƉĂƚŝĞŶƚƐǁŝƚŚƉƌŝŽƌ ĐŽŶĐĞƌŶĞĚĂďŽƵƚŚŝƐƉƌŝŽƌĚĞĐŽŵƉĞŶƐĂƚŝŽŶ ĞƉŝƐŽĚĞŽĨĚĞĐŽŵƉĞŶƐĂƚŝŽŶ͕ŶŽǁ͞ƌĞͲ ĐŽŵƉĞŶƐĂƚĞĚ͍͟ ĂŶƉĂƚŝĞŶƚƐǁŝƚŚƉƌŝŽƌŚĞƉĂƚŝĐĚĞĐŽŵƉĞŶƐĂƚŝŽŶďĞ ƚƌĞĂƚĞĚǁŝƚŚ'ͬWŽƌ^K&ͬs >ͬsKy͕ŝĨŶŽǁŚĞƉĂƚŝĐĂůůLJ ĂŶLJŽƵĞǀĞƌƵƐĞ'ͬWĂŶĚ^K&ͬs >ͬsKyŝŶ ƐƚĂďůĞ͍ ĚĞĐŽŵƉĞŶƐĂƚŝŽŶ;ŽƌƌĞͲĐŽŵƉĞŶƐĂƚŝŽŶ͍Ϳ ϭͿ z ^ ϮͿ EK Ϯ ϭϮͬϰͬϮϬϭϴ 'ͬWΘ^K&ͬs >ͬsKyŝŶĚĞĐŽŵƉĞŶƐĂƚŝŽŶ YƵĞƐƚŝŽŶƐĨƌŽŵƚŚĞƵĚŝĞŶĐĞ ^ĂdžĞŶĂ ^>ϮϬϭϴ sƐƚƵĚLJŽĨ^K&ͬs >ͬsKyƌĞƚƌĞĂƚŵĞŶƚŝŶ͞ZĞĂůǁŽƌůĚ͟ ĞůƉĞƌŝŽ ^>ϮϬϭϴ ϯ AddictionMedicineUpdatefortheHIVPrimary CareClinician Ihavenothingtodisclose KatherineGrieco DO KatherineGriecoDO Outline NEJM • October18th,2018 • Treatmentmodels • Opiates • Benzodiazepines • Alcohol AddictionTreatmentModels ScreeningforSUDin • Harmreduction PrimaryCare – setofpracticalstrategiesandideasaimedatreducingnegative • SBIRT– screening,briefintervention consequencesassociatedwithdruguse – amovementforsocialjusticebuiltonabeliefin,andrespectfortherights andreferraltotreatment ofpeoplewhousedrugs – ModerationManagement • Abstinence – completecessationofalcoholanddrugs. • Individualizedapproach – Safetysensitiveoccupations • Healthcareprofessionals • Airlinepilots • Construction – Risk/benefitratio Asopioidepidemiclevelsoff, CDC:OpioidOverdoseDeaths stimulantuserises. Age-adjusted drug overdose death rates, by state: United States, 2016 • 2017:47,944ODdeaths • 2018:46,655ODdeaths • Opioidoverdosesarenotdeclining,rather,are increasing ataslowerratethantheyhavepreviously. 59,000 to 65,000 CDC:DrugOverdoseDeaths,1980Ͳ2016 people died from drug Drugoverdosesarenowtheleadingcauseof OD in US in 2016 Overdoses Mostcommondrugsinvolvedin deathamongAmericansunderklkl50. prescriptionopioidoverdosedeaths: Peak car crash deaths 1972 Methadone(pillform) Peak HIV deaths 1995 Oyxcodone Hydrocodone Peak gun deaths 1993 2017: >72,000 deaths from drug OD WARNING: Crisis has not peaked (?) CDC:FentanylDeathsin2016:Up540%in3Years Kratom (provisionaldata) Deaths involving synthetic WorsethanHIV opioids, mostly fentanyl, jumped from • TropicaltreeinSoutheastAsia 3,000 to 20,000 in 3 yrs. – Eatleavesraw,crushorbrewedintea,tablets, capsules,liquid • Actsonopioidreceptors – SmallamountsͲ>stimulant Increase in deaths from – LargeramountsͲ>sedative Cocaine & meth use (often involve opiates) – Usersclaimithelpswithpain&opioidwithdrawal • Symptoms(viacasereport) – withdrawal – seizures – psychosis 20002015 Kratom DSMͲ5CriteriaforOpiateUseDisorder 11Criteria–Presenceofatleast2forOUD • DEA– 2017:DrugsofConcernList • FDA–NOTapprovedforany • Missingworkorschool • Usingmorethanintended therapeuticuse • Usinginhazardoussituations • Tryingtoquitwithoutsuccess • Legal– buyonline • Usingdespitesocialorpersonal • IncreaseddrugͲseekingbehavior – Bannedinseveralstates,notCA problems • Interferencewithimportantactivities – FDAworkingwithDEAtoblock • Cravingforopiates • Continuedusedespitehealthproblems shipmentsintoUSA. • Buildupoftolerance 44KratomͲrelateddeaths2014Ͳ2017 • Withdrawalswhentryingtoquit • SendͲouttestinurine • CDC– linktoSalmonella,CA13cases(4/17) Mild:2Ͳ3;Moderate:4Ͳ5;Severe:6or> MATforOpiateUseDisorder–Options Buprenorphine/naloxone–1st Methadonemaintenance Naltrexone– 2nd • Partialopioidagonist (MMTP)–1st • Opioidblocker • Ceilingeffect– resp depression, • Fullopioidagonist • NOriskforODfromNal;risk sedation • HigherriskforOD,sedation tryingtooverrideblockade MedicationAssistedTreatmentand • Films/Pills/Implantable • Liquidform,dailydosing • Pillorinjection(Vivitrol) • Officebasedtx – requiresfederal • FederallyqualifiedOTP(opiatetx • Officebased waivertoRx program) • Ptsw/cravings,notexperiencing otherTx considerations • Stablepts–nopolydruguse, • Highlyregulated,structure withdrawal,notcurrentlyusing supportsysteminplace, • Counselingmandated • StableptsͲ nopolydruguse, psychiatricallystable • Ptsinneedofmonitoring,lackof supportsysteminplace, • MUSTbeinwithdrawaltostart supportsystem,psychiatrically psychiatricallystable(?forpts MAT: Pharmacotherapypluscounseling • Robustdatatosupportefficacy unstable,Failedbupe whohavefailedMMTP/bupe) andbehavioraltherapies • Withdrawalnotnecessarytostart• MUSTbeinwithdrawaltostart • Robustdatatosupportefficacy • Limiteddata Opiatereplacementtreatmentisassociatedwithreducedmortality,lowerHIVtransmission, improvedsocialfunctioning,andreducedcriminalbehavior. XRNaltrexonevsBuprenorphine XRNaltrexoneGuidelines • SAMHSA Ͳ ClinicalUseofExtendedͲReleaseInjectable • JAMAPsychiatry10/18/17 • TheLancet1/27/18 NaltrexoneinthetreatmentofOUD:ABriefGuide • OpenͲlabel,randomizedclinical • OpenͲlabel,randomized trialx12wks controlledtrialx24wks • Officebasedaddictiontx • N=159,Norway • N=570,USA – Comprehensivetx approach • Noninferior to • Bothmedicationsequallysafe • Counseling buprenorphine/naloxone andeffective • Psychiatrictreatmentasneeded • OUDsuiciderisk:10%vs1.3%inthegenpopulation –Enrollmentfolloweddetox –Easeofinductionremainsproblematic • Socialsupport:AA,NA,mutualͲhelpprograms –Avg buprenorphinedose~11mg forXRNal –Nofollowupdatare:overdoseafter –Higherrelapserateupfront stoppingthemedication –Nofollowupdatare:overdoseafter stoppingthemedication LengthofPharmacotherapy?? • Highestriskofrelapsefollowsdetox– first30Ͳ90days • Beyond90days – Veryindividualized Benzodiazepines • Safetostayonindefinitely Longtermtreatment – SideeffectsofMATfairlyminimal resultsinhigher • Ptsrequesttostop ratesofrecovery – Stable – Buprenorphine/methadone • Slowtaperrecommended BZDsandHIVͲ Studies Benzodiazepines • BZDusersinjectedmorefrequently • Psychoactivedrug – injectedmoreheroinandamphetamines,more polyͲdrugusethanotherIDU. • ActsonGABAreceptor • HigherlevelsofHIVriskͲtaking – Inhibitoryneurotransmitter – sharedinjectingequipmentmorefrequentlyand • Sedative,hypnotic,anxiolytic,anticonvulsant,musclerelaxant withmorepeople. properties BenzodiazepineuseandHIVriskͲtakingbehaviour amonginjecting • Chemicalstructure drugusers;DrugandAlcoholDependence.Volume31,Oct1992 • – Benzene+diazepene rings BZDuseindependentriskfactorforHIV seroconversion BenzodiazepineuseasanindependentriskfactorforHIVinfectionina Canadiansetting;DrugandAlcoholDependence.Volume155,Oct1st2015 BZDsandHIVͲ Studies BZDCategories/Equivalencies • HIVinfectionitselfissignificantpredictorofBZD&ZͲdruguse – 76.4%oftheHIVptshadBZDorZͲdrugRx;psychillnesssubstantial riskfactors – Primarilyprescribedbynonpsychiatrists;only31.1%soughtmental healthsupportandreceivedRxfrompsychiatrists. BenzodiazepinesandZͲDrugUseamongHIVͲInfectedPatientsinTaiwan:A13Ͳ YearNationwideCohortStudy;BioMed ResearchInternational,Volume2015 • BZDuseisassociatedwithalowqualityoflifeandhighHIVͲrisk behaviorsamongpatientswithSUD. SubstanceabuseandpsychiatricdisordersinHIVͲpositivepatients: epidemiologyandimpactonantiretroviraltherapy,Drugs,vol.66,2006. Indications Epidemiology Common Lesscommon • 80%ofptsw/sedativeusedisorderuseotherdrugs • Panicdisorder • Musclespasms • 30Ͳ50%ofptsw/EtOH usedisorderwhohave presentedtodetox,useBZDs – theonlypsychiatriccondition • ICU/mechanicalventilation • 44%IVdrugusersuseBZDs • Seizuredisorder • Psychiatricemergencies – tooffsetopiatew/d,commonpractice • – Alcoholwithdrawal Acutepsychosis/agitation – to“comedown”fromacocainehigh • Generalizedanxietydisorder • PriortoMRI,orminorprocedures • Ratioof2:1,women:men • Insomnia • TxͲresistantpsychiatricdiagnosis • Useincreaseswithage – OCD,schizophrenia,bipolar& • MostfrequentlyabusedRxdrug,2ndtoopioids others – Rarelytheinitialorprimarysubstanceofabuse September Overdose 2017 • UseofBZDsalonerarely causeoverdose • Combinationofother sedativescanbefatal – EtOH,opiates(esp MTD) • Opioids+BZDs=synergy(?) vsadditiveeffect – Users:amoreintensehigh – Moreresearchneeded Thecombineduseofthesedrugsincreasestheriskofserioussideeffects;however,the harmcausedbyuntreatedopioidaddictioncanoutweightheserisks. AdverseEffects BZDs&Dementia CognitiveDeficits BehavioralDisturbances • AssociationbetweenBenzodiazepineUseandDementia:A MetaͲAnalysis • Longterm use,deficitsin: • Paradoxicaleffects(1%) – PLoS One.Publishedonline2015May27. – Learning – Aggression,agitation,irritability – Memory • Increaseddepression,suicidality • FindingsconsistentlyindicatelongtermBZDuseisassociated – Attention • CanmimicpersonalityͲdisordered withdementia – Visualspatialability behavior – Anterogradeamnesia • Causal? – Impulsivity,disinhibition • Morecommoninabuse – Emotionaldysregulation – Moreprospectivecohortstudieswithlongtermf/uareneeded. – Unstablemood Dementia Guidelines • 2014:olderadultsusingBZDsforlongerthan • APA,AmericanPsychiatricAssociation 3monthsͲ 51%greaterriskofAlzheimer’s. • AGS,AmericanGeriatricSociety – Anxiety&insomniaoftensxs ofAlzheimer’s – TheBeersCriteria:avoidinolderadults – BUTstillfoundindependentrisk • BAP,BritishAssociationforPsychopharmacology • 4otherpriorstudies(2002Ͳ2012)similar • WFSBP,WorldFederationofSocietiesofBiological Psychiatry results • NICE,NationalInstituteofClinicalExcellence – Increasedriskofdementia,cognitivedecline Prescribewithcautionesp inelderlyorptswith h/oaddiction,andforshorttermuseonly. BMJSeptember9,2014;BMJ2012;345:e6231;AmJGeriatr Psychiatry.2009Jul;17(7):614Ͳ20; PsychologicalMedicine/Volume35/Issue03/April2005,pp307Ͳ315;JournalofClinical EpidemiologyVolume55,Issue3,March2002,Pages314–318 Howlongistoolong? Tolerance (beforew/doccurs) • Hypnoticeffects • Therapeuticdose: – Fewdaystoweeks – ~10days– insomnia – Commontoincreasedosage • Anxiolyticeffects – ~2weeks– reboundanxiety – Months • Anxietysxs worsethanpriortotreatment – Longterm usedoeslittletocontrolanxiety;mayaggravate – ~2months– mildwithdrawal – Often2BZDstaken;justpreventsw/d,ratherthanreduceanxiety • Recommendation: • Anticonvulsant&musclerelaxanteffects – Fewweeks – ShorttermRxonly • Cognitivedeficits/dementia/amnesiceffects – Prescribenolongerthan2Ͳ4wks – Verylittletolerance – Capmaximumdose(2mgin24hrs) BZDWithdrawalSxs WithdrawalTimeframe MEDICAL PSYCHIATRIC • ShortͲactingBZDs:alprazolam,oxazepam,temazepam • Variable • ReboundAnxiety – w/donset12Ͳ24hrs • fewobservablehyperadrenergic • Restlessness signs/vitalsigndisturbance – Sxs peak1Ͳ5days • Perceptualdistortions/hallucinations • Seizures – Durationofacutew/d7Ͳ22days • Palpitations• Sensoryhypersensitivity • Headaches• Tinnitus • LongͲactingBZDs:diazepam,chlordiazepoxide • Muscleaches/twitches • Flushing• Confusion/delirium – w/donset3Ͳ5days • Poorsleep – Sxs peak1Ͳ9days • Sweating • Dizziness – Durationofacutew/d10Ͳ28days BZDWithdrawal OutpatientTaper • Historicallyw/dhasbeenpoorlymanagedͲ>acquired • SwitchtolongͲactingagent reputationasatraumaticprocessforbothpatientAND – Clonazepam,Chlordiazepoxide,Diazepam provider. • Decreaseby10Ͳ25%weekly • ManagementofBZDw/dextensivelyreviewed:allagree – Example:alprazolam1mgQID – Gradualdosagetaper • Decreaseby0.5to1mgweekly • Longterm users:6mos to1year – Psychologicalsupport! • Taperupto6monthstoayear(s) • Exception:illicituse,highͲriskabuse • Addsupportivemeds – Inpt detox–average5Ͳ10days,longactingBZDtaper OutpatientTaper Supportivemeds Foruseduringtaper/detox • Psychologicalsupport • Insomnia – CBT,mindfulness – Trazodone50mgPOQHSPRN • Discussthetaperseveralvisitspriortothedaythetaperstarts – Mirtazapine15mgQHS – Diphenhydramine50mgPOPRN – Educatept:risksoflongterm use/benefitsoftaper • Anxiety – Workasateamwiththept tochoosetheday,andthedosage – SSRIs/antidepressantsfirstline! decreaseperweek – Clonodine 0.1mgTIDPRN • Acupuncture(“acudetox”) – Buspirone 5mgTID – Hydroxyzine100mgPOevery8hrs PRNanxiety – Blockshormonesassoc w/stress – Propranolol10mgTID(canincreasedoseasneeded) – Auricularpointsreducecravings – Usewithcaution • Seroquel • Gabapentin Overdosetreatment InteractionswithHIVmeds • Flumazenil • ProteaseInhibitors/NNRTIs • IntegraseInhibitors – Midazolam,triazolam – SameconcernsasPIs/NNRTIs – GABA–Areceptorantagonist • SignificantјBZDs – reversestheeffectsofBZDs • DoNOTcoadminister – Exception:RALok – – UsedinER/hospitalsettings Alprazolam,diazepam • BZDlevelsmayј • Reversedrowsinessafterprocedures – Alt:lorazepam,oxazepam,temazepam (LOT) – Riskofwithdrawalseizuresindeppts • NonͲCYP450pathways • Preferredinliverdx&elderly – Zolpidem,Eszopiclone • CYP4503A4pathway • MayincreaselevelsofZdrugs Alcohol&HIV • RateofAlcoholAbuse – generalpopulation:4.6%,VSHIV:8%(2x) • Increasesviralreplication – Mayincreaseimmuneactivation,inflammation – Mayincreaseconcentrationinsemenandvaginalsecretions Alcohol • Increaseinunhealthydrinkingassociatedwithpoorer outcomes:lowerCD4,higherVL • EtOH effectsonARV – Liverdamage – Adherence • Ptswhodrink9moretimeslikelytofailtoadheretoregimenvssober • Interactions?:1in4HIVptsbelievethis;skipdoseswhiledrinking NIAAA;AlcoholAlertNumber80;WilliamsEC,McGinnisKA,Bobb JF,etal.ChangesinalcoholuseassociatedwithchangesinHIV diseaseseverityovertime:anationallongitudinalstudyintheVeteransAgingCohort.DrugAlcoholDepend.2018;189:21–29. AlcoholScreeningTools CAGEScreen • HaveyoueverfeltyouneededtoCutdownonyour • CAGE drinking? • AUDIT • HavepeopleAnnoyedyoubycriticizingyourdrinking? • CRAFFT • HaveyoueverfeltGuiltyaboutdrinking? – Adolescents • Haveyoueverfeltyouneededadrinkfirstthinginthe • morning(EyeͲopener)tosteadyyournervesortogetrid Singlequestionscreen: ofahangover? • “Onanysingleoccasionduringthepast3months,haveyouhad • Scoreof>2: morethan5drinkscontainingalcohol?” – Specificityof76%,sensitivityof93%:identificationofexcessive – identifiespatientswhomeetcriteriaforatͲriskdrinkingoralcoholabuse drinking ordependencespecifiedinDSM–IV. – Specificityof77%,sensitivityof91%:identificationofEtOH dep AUDIT(WHO) What’sastandarddrink? • HazardousEtOH 12fl oz = 8Ͳ9fl oz of = 5fl oz of = 1.5fl oz shot consumption regular maltliquor table 80Ͳproofspirits beer (12Ͳozglass) wine ("hardliquor") – >8men – >7women • EtOH dependence – >20 ~5% ~7% ~ 12% ~ 40% alcohol alcohol alcohol alcohol What’s“atͲrisk”drinking? PEth Test • Variesbasedongender • PhosphatidylEthanol test • Dailylimits • directbiomarker • Weeklylimits • phospholipidformedinthe RBCmembraneexclusively inthepresenceofethanol • Detectionperiodofupto3Ͳ4wks PEth Test DUI #DUIArrests Medical Criminal • Highdiagnosticsensitivityandspecificityfordetecting 1 50%chanceSUD AlcoholEducation activechronicexcessivedrinkingbehaviors Program* – regulardailyalcoholintakeofmorethan60g(4Ͳ6drinks) 2 90%chanceSUD Misdemeanor – onestandarddrinkcontains10Ͳ14 gramsofalcohol,andisequivalent Conviction 3 Diagnostic SUD Felony** tooneordinarybeer,asmallglassofwine(100mls)oranipofspirits SecondConviction (30mls) * Estimate driven approx 60 times under influence before arrested. ** May be considered a second first conviction. By the time there is a felony conviction, there are at least 3 arrests. DSMͲVCriteriaforAlcoholUseDisorder ClinicalApplication 11Criteria–Presenceofatleast2forAUD • MildAUD notinneedofdetox • Missingworkorschool • Drinkingmorethanintended +/Ͳ pharmacotherapy • Drinkinginhazardoussituations • Tryingtoquitwithoutsuccess +mentalhealthreferral/counseling • Drinkingdespitesocialorpersonal • IncreasedalcoholͲseeking • ModerateAUD problems behavior +/Ͳ detox(h/ow/dwhenpt attemptstostop?) • Cravingforalcohol • Interferencewithimportant +pharmacotherapy +mentalhealthreferral/counseling • Buildupoftolerance activities • SevereAUD • Withdrawalswhentryingtoquit • Continuedusedespitehealth problems +detox +pharmacotherapy +mentalhealthreferral/counseling Mild:2Ͳ3;Moderate:4Ͳ5;Severe:6or> StagesofAlcoholWithdrawal Hallucinations–whentobeconcerned STAGE Symptoms Management Notes I– Mild Shaking,elevated Outpatient Ptshouldbe • AlcoholHallucinosis Within24hrs pulse&BP,GI management; monitoredby – ~24hrs afterlastdrink,lastsfor24hrs. upset,agitation dailyvisits(RN) family/friendwho 5days will stayw/pt – 25%ofptswithprolongedh/oEtOH abuse throughoutdetox – Tactile,visualhallucinationsmostcommon IIͲModerate StageIsxs PLUS Outpatient Verydifficult to – Otherwisesensoriumisclear;insight 24Ͳ36hrs hallucinations managementif diagnose; withinsight pt revertsto Recommend – NotnecessarilyfollowedbyDTs StageIin3hrs inpatientdetox • DeliriumTremens III– Severe StageIsxs PLUS Inpatient 5Ͳ10daydetox >48hrs hallucinations Detox/ICU – ~48Ͳ72hrs afterlastdrink without insightͲ – Profoundlyalteredsensorium DeliriumTremens • Disorientation,agitation,hallucinations – Severeautonomicderangements • јBP,јHR,јRR,diaphoresis,hyperthermia PrinciplesofAddictionMedicine,Ries,Fiellin etal WithdrawalSeizures WithdrawalTx (Detox)Ͳ Outpatient • Withdrawalseizures • Benzodiazepines –mainstay – ~24hoursafterlastdrink – ShortͲacting – 23%Ͳ33%ofptsw/severeEtOH withdrawal • Diazepam,lorazepam(preferredinliverdx,geriatric) – Brief,generalized,tonicͲclonic,noaura – LongerͲacting – 30%Ͳ50%progresstoDTs • Chlordiazepoxide • Rarelyabused • AcuteTx • SupportiveTx – benzodiazepine – • lorazepam2mg Clonidine0.1Ͳ0.2mgTID • • Diazepam10mg Combatsadrenergicdischarge:HTN,tachycardia,tremor – sendtoER – AntiͲdiarrheal,antacid,NSAIDs Chlordiazepoxide Gabapentin OutpatientTaper OutpatientTaper • Foruncomplicatedalcoholwithdrawal Schedule Day1Day2Day3Day4 Rigid 50Ͳ100mgQID 50Ͳ100mg 50Ͳ100mg 50Ͳ100mg TID BID QHS • 400mgTIDx3days Flexible 50Ͳ100mgQ4Ͳ6 50Ͳ100mgQ 50Ͳ100mgQ 50Ͳ100mg hrs PRN 6Ͳ8hrs PRN 12hrs PRN QHSPRN • 400mgBIDx2days Front 100Ͳ200mgQ2Ͳ4 50Ͳ 100mgQ 50Ͳ100mgQ None loading hrs untilsedation 4Ͳ6hrs PRN 4Ͳ6hrs PRN • 400mgQdailyx1day isachieved;then 50to100mgQ4Ͳ6 hrs PRN OutpatientMeds EtOH Pharmacotherapy • VitaminDeficiencies – MVI:onedaily • Naltrexone (POandIM)Ͳblocksmureceptors.50mgPOQD,380mgIM q4wks.Nausea,HA,dizziness,LFTs.1st line – Thiamine(Vit B1):100mgdaily – Vivitrol:monthlyinjection – Folate(Vit B9):1gmdaily • Insomnia,anxiety • AcamprosateͲincreasesGABAandeffectsglutamateneurotransmission. – Trazodone50Ͳ100mgQHS Decreasescravings,666mgTID,GI,pruritis – Hydroxyzine50Ͳ100mgQID nd – Propranolol20Ͳ40mgBID • Disulfuram –blocksaldehyde dehydrogenase.2 line,avoidinCAD, pregnancy,cognitiveimpairment • MonitorBP,HR;cautioninasthma,cocaineusers • Gabapentin –offlabeluse • NoconcerninginteractionswithHIVmeds ComprehensiveTreatmentApproach • Counseling • Psychiatrictreatmentasneeded – 30Ͳ40%ofptswithAUDhavemajordepression – EtOH+depression:suiciderate11% – Depressionalone:suiciderate0.5% • Socialsupport:AlcoholicsAnonymous NarcoticsAnonymous RefugeRecovery RecoveryYoga • PtswhoattendAAare50%morelikelytobeabstinentvsnonͲattendees. 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ƉĐůƵƐĂͿ͘ яяя ůĞĚŝƉĂƐǀŝƌ ;>sͿ E^ϱŝŶŚŝďŝƚŽƌ ϲ DĂǀLJƌĞƚ ŐůĞĐĂƉƌĞǀŝƌ ;'> Ϳн E^ϯͬϰƉƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌн ϭ͕Ϯ͕ϯ͕ ,s͗ddžͲŶĂŢǀĞ͕'ƚϭĂ͕ƐƚĂŐĞϮĨŝďƌŽƐŝƐ͕ŶŽ яdWͲ ;яͿ ƉŝďƌĞŶƚĂƐǀŝƌ ;W/Ϳ E^ϱŝŶŚŝďŝƚŽƌ ϰ͕ϱ͕ϲ ĐŝƌƌŚŽƐŝƐ;WZ/сϬ͘ϯͿ͕,ss>сϭϬŵŝůůŝŽŶ sŽƐĞǀŝ ƐŽĨŽƐďƵǀŝƌ ;^K&Ϳн E^ϱŝŶŚŝďŝƚŽƌн ϭ͕Ϯ͕ϯ͕ ǀĞůƉĂƚĂƐǀŝƌ ;s >Ϳн E^ϱŝŶŚŝďŝƚŽƌн ϰ͕ϱ͕ϲ dWͲ ;ZsͿ >ĂďƐ͗EŽƌŵĂůůŝǀĞƌĨƵŶĐƚŝŽŶ͕ƌůсϳϱ ǀŽdžŝůĂƉƌĞǀŝƌ ;sKyͿ E^ϯͬϰƉƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ DĞĚƐ͗ ĞƉĂƚŝĞƌ ĞůďĂƐǀŝƌ ; ZͿн E^ϱŝŶŚŝďŝƚŽƌн ϭ͕ϰ яdWͲ ŐƌĂnjŽƉƌĞǀŝƌ ;'ZͿ E^ϯͬϰƉƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌ ± d&ͬ&dͬ &s͗ϭƚĂďůĞƚŽŶĐĞͲĚĂŝůLJ ± KŵĞƉƌĂnjŽůĞ͗ϮϬŵŐŽŶĐĞͲĚĂŝůLJ Ϯ ϭϭͬϯϬͬϮϬϭϴ ĂƐĞηϭZĞĐŽŵŵĞŶĚĞĚ YƵĞƐƚŝŽŶηϭ͗tŚŝĐŚZsƐŚĂǀĞĂŵĂũŽƌ dƌĞĂƚŵĞŶƚKƉƚŝŽŶƐ͗ ĚƌƵŐͲĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶǁŝƚŚ^K&ͬs > ddžͲEĂŢǀĞ͕,s'ƚϭĂ͕ŶŽƚĐŝƌƌŚŽƚŝĐ ; ƉĐůƵƐĂͿ͍ ZĞŐŝŵĞŶƐ ŽƐĞ ƵƌĂƚŝŽŶ Ă͘ ĨĂǀŝƌĞŶnj Zͬ'ZΎ YĨŝdžĞĚͲĚŽƐĞĐŽŵďŽ Z;ϱϬŵŐͿͬ'Z ;ϭϬϬŵŐͿ džϭϮǁĞĞŬƐ ď͘ ĂƌƵŶĂǀŝƌͬƌ '> ͬW/ YĨŝdžĞĚͲĚŽƐĞĐŽŵďŽ'> ;ϯϬϬŵŐͿͬW/ ;ϭϮϬŵŐͿ džϴ ǁĞĞŬƐ ^K&ͬ>sΎΎ YĨŝdžĞĚͲĚŽƐĞĐŽŵďŽ^K&;ϰϬϬŵŐͿͬ>s;ϵϬŵŐͿ džϭϮǁĞĞŬƐ Đ͘ dĞŶŽĨŽǀŝƌĂůĂĨĞŶĂŵŝĚĞ ^K&ͬs > YĨŝdžĞĚͲĚŽƐĞĐŽŵďŽ^K&;ϰϬϬŵŐͿͬs >;ϭϬϬŵŐͿ džϭϮǁĞĞŬƐ Ě͘ ůǀŝƚĞŐƌĂǀŝƌͬĐ Ύ/ĨŶŽďĂƐĞůŝŶĞE^ϱZsƐĚĞƚĞĐƚĞĚ;ĨŽƌ ZͿ Ğ͘ ůůŽĨƚŚĞĂďŽǀĞ ΎΎdžϴǁĞĞŬƐŝĨ,ss>фϲŵŝůůŝŽŶ͕ŶŽŶͲďůĂĐŬ͕,/sƐĞƌŽŶĞŐĂƚŝǀĞ DĞĐŚĂŶŝƐŵŽĨ^K&ͬs > ^K&ͬs >; 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HIVE NationalPerinatalHIVHotline ReproductiveHealthisaHumanRight. • WithintheframeworkofWHO'sdefinitionofhealthas astateofcompletephysical,mentalandsocialwellͲ Natl PerinatalHIVHotline being,andnotmerelytheabsenceofdiseaseor infirmity,reproductivehealthaddressesthe &CliniciansNetwork reproductiveprocesses,functionsandsystematall 1Ͳ888Ͳ448Ͳ8765(24/7) stagesoflife.Reproductivehealth,therefore,implies ReproID_HIVlistserv thatpeopleareabletohavearesponsible,satisfying [email protected] andsafesexlifeandthattheyhavethecapabilityto reproduceandthefreedomtodecideif,whenand howoftentodoso. http://www.who.int/topics/reproductive_health/en/ WorldHealthOrganization,accessedOct31,2018 ProvisionofReproductive Peoplefirstlanguage HealthcareisOurObligation. #LanguageMatters “#NotYourInfection isimportanttomebecausepeople Implicitinthisaretherightofmenandwomen livingwithHIVdeserverespect.Awordcanbecorrect, tobeinformedofandtohaveaccesstosafe, butthatdoesn’tmakeitnice.IamlivingwithHIV,notan HIVinfected person.IamNOTaninfection!” – effective,affordableandacceptablemethodsof Mina,ateenlivingwithHIV fertilityregulationoftheirchoice,andtheright ofaccesstoappropriatehealthcareservices • PersonlivingwithHIV(PLHIV) • Woman/ManlivingwithHIV(W/MLHIV) thatwillenablewomentogosafelythrough • PerinatalHIVtransmission pregnancyandchildbirthandprovidecouples • Serodifferent couple withthebestchanceofhavingahealthyinfant. • GenderͲexpansiveandinclusivelanguage http://www.who.int/topics/reproductive_health/en/ https://hiveonline.org/wpͲcontent/uploads/2016/01/AntiͲStigmaSignͲOnletter1.pdf WorldHealthOrganization,accessedOct31,2018 HIVepidemiologyhighlights ReproductiveHealthcare structuralracism • Amongwomen,newdiagnoseswashighest Mypartner/IwanttogetpregnantÆ Preconceptioncare amongBlackwomen(43per100,000); IampregnantÆ Prenatalcare comparedtowhitemen(39per100,000) Mypartner/Idon’twanttogetpregnantÆ Contraception • Blackwomenrepresent6%ofSFfemale population and37%ofWLHIV IwanttoendmypregnancyÆ Accesstosafeabortion • Blackwomenhadamortalityrateof43 Idon’tknowwhatIwantÆ Preconception/contraception deathsper100,000–4.5and7.5timesthatof Latinx andwhitewomen. IwanttofindapartnerÆ http://www.hivdatingsites.biz 2017SFHIV Epidemiology AnnualReport Iwantasatisfyingandsafesexlife. Reproductivehealth=primarycare Everyinteractionisanopportunity. • Ifwesucceedatintegratingpreconceptionand familyplanningintoprimarycaremodel • Tocheckinaboutsex – EveryHIVͲexposedpregnancywillbeplannedand • Toassessdisclosuretopartners wellͲtimed. • TodiscussHIVstatusandtestingofpartners – TherewillbenoHIVtransmissiontosexualpartners. – TherewillbenoHIVtransmissiontoinfants. • ToassessadherenceandremindaboutTasP – ThehealthofallHIVͲaffectedparentsandinfants • ToeducateaboutPEPandPrEP willbeoptimized. • Todiscussreproductivehealthdesires – Wanttohaveachild? – Wanttoavoidhavingachild? HIVE:ahubofpositivesexualand reproductivehealth www.HIVEonline.org www.HIVEonline.org Sexual/ReproductiveHistory ReproductiveDesires/Intentions sex/genderofpartners,types/frequencyof Reproductivedesires sex,numberofpartners,concurrent Doyouwanttohavechildreninthefuture? partnerships/sexualagreements,condomuse, Ifnoand“atrisk”ofpregnancy/impregnating, contraception(prn),concurrentdruguse contraceptiveuse? satisfyingsexlife?agencyaroundsex? Reproductiveintentions pastpregnancies(selforpartner/s): Ifso,whatwouldbeyouridealtimeline? planned/desired?,outcome discussionaboutpartnerHIVstatus,safe historyofSTIs(self andpartner/s) conception,birthspacing(atleast12Ͳ18months betweenbirthͲpregnancy) historyoftrauma surrogacy,fostercare,adoption,alternativefamily buildingoptions PregnancyandTGHealth • HIVEVideo – https://www.hiveonline.org/junoͲobedinͲmaliverͲ onͲreproductiveͲhealthͲforͲtransmen/ https://www.hiveonline.org/ wpͲ content/uploads/2015/06/Tr ansMenFertility.pdf FertilitydesiresamongPLHIV USreproductiveͲagedwomen 35% WLHIV US,HCSUS 20Ͳ29% (59%) Rochester British Columbia (Baltimore) Eurosupport V 45% MLHIV(MSW) US, HCSUS 28% WEWANTTOGETPREGNANT! Eurosupport V 41% Predictors: age<30y,childless(metaͲanalysis20studies) ¹ChenFam Plann Persp 2001,²StanwoodContraception2007,³OgilvieAIDS2007,4OladapoJNatl Med Assoc 2005,FinoccharioͲKesslerAIDSBehav 2010;Nöstlinger 2013;Berhan BMCPublicHealth 2013, Sherr JIAS2010 Whoinfluencesreproductive DesiresamongMSMwithHIV? desiresofWLHIV? • n=84,UK • UMiami,n=49WLHIV • 77.6%nodiscussionwithadoctor • KAPsurveyre:fertilityplanning,reproductive desires,andsaferconceptionpractices aboutbecomingaparent • youngerandlesseducationinfluencedby • 68.2%feltnotsufficientlyinformed partners’desires • olderandmoreeducationinfluencedby physicianendorsementofchildbearing www.GaysWithKids.com Jonesetal.PLOSOne,Sept2016 Sherr L,BarryN:FatherhoodandHIVͲ overlookedandunderstudied.Abstractno. 1034.2ndIASConferenceonHIVPathogenesisandTreatment.2003 Pregnancy,HIVandTransgender GoalsofHIVͲinformedpreconception Health care • PubMedsearch“pregnancyHIVtransgender” • Preventunintendedpregnancy – Oct2018:n=12articles – Only1articleaboutpregnancy,HIVandTGhealth • PreventHIVtransmissiontopartner – Viralsuppression,PEP,PrEP • Optimizematernal&paternalhealth – Vaccination,OIprophy,smokingcessation,etc • Improvematernalandfetaloutcomes • PreventperinatalHIVtransmission ACOG PracticeBulletinNo117;December,2010 Preconceptionmanagement Takeadvantageofthedesiretoget • Antiretroviraltherapy – NotonART?Æ startbeforeattempting pregnant/conceiveasan conception,esp ifserodifferent opportunitytooptimizehealthand – Whattostart???(moreonthisinamoment) • Folate (400mcg)orprenatalvitamins encourageotherforwardͲthinking • OIprophylaxis behavior. – TMPͲSMXandNTDrisk • 4Ͳ10mgfolate (vs.deferconceptionuntil CD4>200x3mos) – Azithro (vs.deferconceptionuntilCD4>100x 3mos) WhatARV(s)arenot Preconceptionmanagement recommendedamongwomen • Screen/treatSTIs seekingconception? • Vaccinateprn • Optimizenutrition,exercise • 1.DTG • Addresstrauma • 2.COBI • Addresstobacco,drug,alcoholuse • 3.EFV • Comprehensivemedreview(includingOTC,herbs,etc) • Engagingthepartner • 4.RPV – HIVandSTItesting • 5.DTGandCOBI – PEP,PrEPeducation,prescriptionprn – Linkagetocare • 6.DTGandEFV – Smokingcessation,drugtreatment • Testingchildren • 7.Alloftheabovearetobeavoided DoweneedtoavoidDTGin preconceptionperiodand pregnancy? Zash NEJMJuly2018 Botwana ARV/pregnancy WHO:EFVbackas1st linefor surveillance:4NTDcasesin6m womenofchildͲbearingpotential AnEFVͲbasedregimenisasafeandeffective1stͲlineregimen recommendedforusebytheWHO2016ARVdrugguidelinesandcanbe usedamongwomenofchildbearingpotentialduringtheperiodof potentialriskfordevelopingneuraltubedefects(atconceptionandupto 8weeksafterconception). Zash NEJM2018 Letwomenmakeinformed AvoidCOBI(+EVGorDRVorATV) choices. amongwomendesiringconception? • IMPAACT1026;intensivepK,n=30 • Pregnancyvs.postpartum • COBIÐ 44%in2nd tri,Ð59%in3rd • EVGAUCÐ 24%in2nd tri,Ð44%in3rd • COBI/ATVnotstudiedinpregnancybutsamepK issuesexpected • Implicationsforthose“atͲrisk”forconception? • Counselre:possibleneedtoswitchARVinfuture pregnancy • Genvoya,Stribild,Prezcobix,Symtuza,Evotaz Momper AIDS2018 AvoidRilpivirine preͲconception? • Levelsvariableamongpregnantwomen • TotalRPVAUC~30to40%Ð duringpregnancyvs.postpartum • Unbound(pharmacologicallyactive)lessaffectedbypregnancy • ~10%womentrough<EC90(levelneededtoinhibit90% replication)….90%trough=OK • FDAOct2018ODEFSEYlabel:“Forpregnantpatientswhoare alreadyonODEFSEYpriortopregnancyandarevirologically suppressed(HIVͲ1RNAlessthan50copiespermL),onetabletof ODEFSEYtakenoncedailymaybecontinued.Lowerexposuresof rilpivirine,acomponentofODEFSEY,wereobservedduring pregnancy,thereforeviralloadshouldbemonitoredclosely.” • SamerecommendationsaddedtotheCOMPLERAlabel. I’MPREGNANT! FDAOct2018;EkeJAIDS2018;Osiyemi Inf DisTher 2018;Schalkwijk CID2017 MaryisonDolutegravir MoreaboutMary • MaryisalongͲtermpatientofyours,living • Marysaysherperiodisirregularbutthinksit withfamilyoutͲofͲstateforayear,backnow. was~2Ͳ3monthsago. • 32yowithviralsuppressiononTDF/ABC/DTG • Reflexurinepregnancytest:Positive for3years. • Maryisthrilledandexpressesdesireto • PanͲsensitiveHIVbutadherencedifficultin thepastwhenonnonͲsingleͲtabregimens continuepregnancy.(N.B.noassumptions aboutwomen’sreactionstoandplansfor • Aspartofclinicvitalsigns,thenurseasks timingofLMP(greatidea,ifyoudon’talready pregnancy) dothis) SameͲdayultrasoundshowsMary What’syournextstep? is12wpregnant.Whatnext? 1. ScheduleanappointmentwithOBwithin • 1.Feelgratefulyoudidn’tchoseOBasa next7days. specialtyandcalltheNationalPerinatalHIV 2. SwitchtoTDF/FTC+RAL. Hotlineforadvice. 3. ContinueMaryonTDF/ABC/DTGbecauseit • 2.ContinueDTG hasworkedforherandotherregimenshave • 3.SwitchfromDTGtoRAL not. • 4.StopARVsandresumethemin2weeks 4. ObtainsameͲdayultrasoundanddiscuss switchingoffDTGbasedonthat. Afterwhatgestationalageisitok toinitiateorcontinueDTGduring GestationalageandDTGrisk pregnancy? • Neuraltubedefectsdevelopwithin4weeks • Itdependswhichguidelinespanelyouask… afterconception(6weekspostͲ LMP/gestationalage) • 2ofthe4defectsinBotswanapossibly“postͲ neurulation”(i.e.betweenneuraltubeclosure andtheendofthe1st trimester) • 1st trimesterendsat12wks vs.14wks dependingonwhomyouaskandifyoudefine basedonconceptionagevs.LMPage “OK”timingofDTGuse IfMaryweremypatient,I’doffer: PostͲ PostͲLMP • ContinueDTG(NTDhappenч4weeksofconceptionor conception (what’scalled ч6weeksfromLMP) “gestational • SwitchDTGÆ RALvs.ATV/r age”inUS) • SwitchtoEFVͲbasedsingleͲtabregimen WHO(07/18) 8wks 10wks • ConsiderRPVsingleͲtabregimen,thoughassociated withÐ pK in2nd and3rd trimester AdultARV guidelines(05/18) 8wks 10wks AdultARVguidelines(10/18) 12wks 14wks • Personalpractice:don’ttrytoohardtoconvince PerinatalARVguidelines(11/18) (10Ͳ)12wks (12Ͳ)14wks ** womantostopDTGevenif<12weeksifotherwise workingforher **PanelmemberswouldconsiderusingDTGat10weekspostͲ • Tivicay,Juluca, Triumeq conception/12weeksgestationalagebyLMPbasedonan individualpatientbasis. WhattodoforacuteHIVduring Sarahbecomesyourpatient pregnancy? • Sarahis31yoG2P0at30weeksgestation 1. Panic 2. Ihavenoidea,butI’llcalltheNationalPerinatal st th • 1 triroutine4 genHIVAg/Ab negative HIVHotline. • 3rdtriroutine4th genHIVAg/Ab positive 3. Startcoformulated 3TC/ABC/DTGASAP 4. StartTRV/DTGASAP • Whattodo??? 5. StartTRV/RALASAP 6. Repeatthetestin1weektoconfirmdx 7. ObtaingenotypeandinitiateARTonceresults return AcuteHIVduringpregnancy ARTtimingÆ VLdecayÆ transmission • Highriskofperinatal(andsexual,lactational)transmission • StartARTASAP UK/Ireland 0.1% <50copies@delivery • Goal=rapidviraldecay(frequentserialVL“stat”) France Nocases preconceptionor1st tristartand<50copies – n=90;ARTinitiation>20wks @delivery – Mediantime1Ͳlogdecay:INSTI=8dvs.nonͲINSTI=35d 0.5% 14Ͳ27wkstartand <50copies@delivery • DTGvs.RAL – BothpromotedtoPREFERREDafter12wks OR23.2 >500copiesat~30wks – Adherence=critical;oncedailyDTGvs.BIDRAL So.Africa OR0.92 perweekofART – HigherbarriertoresistanceDTG – Avoid3TC/ABCcoͲformulationvs.riskAHRwhileawaitHLA • Startasearlyascantolerate… test? • ConsiderDOT(inpatientoroutpatient) • Aggressiveoptimization/adherenceinterventionsif – 3rd trimesterDOT=costͲeffective slowdecay(<1logby4weeks)orviremic in3rd trimest Rahangdale AJOG2016;HightowerAAC2011;McCabePlos One2010 TownsendAIDS2008;HoffmanJAIDS2010;Tubiana CID2010,Tubiana CROI2011 Initiating ART in Pregnancy (aka prescribe what they will take) NRTI/ NNRTI PI EI/II NtRTI WhattoStartforARVͲnaïve ABC ATV/r RAL(BID) Preferred F(3)TC DRV/r PregnantWoman DTG>12w TDF (BID) EFV LPV/r(3 Alternative ZDV tabsBIDin RPV 3rd) Not DRV/COBI DTG<12w recommended ATV/COBI EVG/COBI Insufficientdata TAF BIC BecomingpregnantonART AntiretroviralPregnancyRegistry • Discusswhatisknown/notknownaboutrisks – AntiretroviralPregnancyRegistryInterimReport –1Ͳ800Ͳ258Ͳ4263 www.apregistry.com • ConsiderpK changes –www.apregistry.com – MorefrequentVLmonitoring • HIVE:monthlyVL,regardlessofhx,regimen –NowonͲlinepatientenrollment – Aggressiveevaluation/optimizationifviremic – TDM? –ReportWLHIVorwomentakingPEP • EVG/COBI,DRV/COBI,ATV/COBI orPrEPduringpregnancy – If“virallysuppressedandpresentontheseregimens,itis appropriatetoconsidercontinuingthemwithincreased –Interimreportsevery6months viralloadmonitoringifthereareconcernsabout switching” AntepartumCare Intrapartum Care • ART+adherencecounseling – OIprophylaxis:azithro forMAC • Ifrecent viralload<1000copies • Monthlyviralload,including@term – NoIVAZT(unlessveryrecently<1000copies) – UBCcohort(n=318):<50copiesat34wkÆ Viremic @delivery – 6%withviralrebound;meanVL513copies;2%VL>1000copies – Trialoflaborok – 50%ofwomenwithreboundwithin1daybeforedelivery • Prenatalvitamins(counselre:timing) • ContinueoralARVsevenifNPO – e.g.DTG2hrbefore,6hr afterPNV • • TDaP,fluvax;otherinactivatedvax prn ElectivecesareanifnoROM,nolaborand • Contraceptionplan 38+weeksandVL>1000copies • Discussionofbreastfeedingrisk – Formula – Bankedhumanmilk(www.hmbana.org) – HarmreductionandbreastfeedingonART Boucoiran ObGyn 2017;Levison CID2014 Alternatively… PostpartumCare PleasegetRNA<1000copies! • ARTadherencesupport • ConsiderinpatientDOT – MaylosemotivationtotakeART • – CostͲeffectivefor3rdtrimester Offercabergoline lactationsuppression(1mg) • Infantfeeding:formula,bankedhumanmilk • ConsiderRALorDTGͲbasedART – https://www.hmbana.org – rapiddecay>1log/wk – Harmreductionapproachifconsideringbreastfeeding* • AggressiveoptimizationofART • Contraception • InfantPEP • Closelytrackviraldecaywithexpedited viral – 4wks AZTifconsistentmaternalviralsuppression load – Ifmaternalviremiain3rd trimesterand/ordeliveryÆ call NationalPerinatalHIVHotline Hegazi IntJSTDAIDS2013;WestlingAIDSPatientCareSTDS.2012;TaylorIntJSTDAIDS 2011;PinnettiJAntimicrobChemother2010;McCabePlos One2010 *Levison CID2014 HarmͲreductionapproachto TakeItHome… breastfeeding • Reproductiveandsexualhealthcareisprimary healthcare • Womenwhodesirepregnancyorare“atͲrisk” ofpregnancy – DTGnotrecommended(1st triissues) – COBInotrecommended(2nd/3rd triissues) – RPVokbutmaybenotideal(unlessidealforher) TakeItHome… TakeItHome • WomenwhogetpregnantwhileonART • AggressiveoptimizationofART,adherencefor – DTG:continueif>12Ͳ14wksgestationalage viralsuppressionby3rd trimester • Switchvs.continueif<12Ͳ14wksdependingonher circumstances • Harmreductionapproachtoinfantfeeding – COBI:switchvs.continuewithfrequentVL,TDM – RPV:probablyoktocontinuewithfrequentVL, • Informedfreechoicere:ARTandreproductive TDM healthcare • WomenstartedonDTGinpregnancy:discuss importanceoffuturepreconceptioncarefor subsequentpregnancies Resources Additionalrelevantslides • HIVE • pK andpregnancy – www.HIVEonline.org • HIVprovidersandreproductivehealthcare • NationalPerinatalHIVHotline/Clinicians’Network – www.nccc.ucsf.edu • Saferconception • ReproIDHIVlistserv • Contraception – [email protected] • Screening/treatmentforcervicaldysplasia • 2017PerinatalARVGuidelines(Oct19,2017) • HPVvaccination – www.aidsinfo.nih.gov Gratitude pK andPregnancy • ManyPIsÐ AUCin2nd/3rd tri(troughok) • Doseadjustmentsuggested – ATV/r:300/100vs.400/100daily (2nd/3rdtri) – DRV/r:600/100BID • FrequentVLmonitoring,considerTDM – RPV • Notrecommended HIVPROVIDERSDISCUSSING – COBIͲcontainingregimens REPRODUCTIVEDESIRESWITH PATIENTS LeAntivir Ther.2015;Colbers Antivir Ther.2015;Kreitchmann JAIDS2013; Stek JAIDS2015;SantiniͲOliveiraAAC2014;BestJAIDS2010;Schalkwijk AIDS2016 Whendoprovidersaskmale PROͲMenSurvey patientsaboutreproductiveissues? • OnlineanonymousREDCap survey • Healthcareprovidersdoingprimarycarefor PLHIVinSFBayArea • n=72 • 87.5%MD/DO,12.5%NP • 59%public,35%private,13%VA Orlando,JANAC2017 Howoftendoprovidersask? SAFERCONCEPTION • Videos: – HIV+Men:HavingaHealthySexLifeandHealthyFamily – Adherence – Disclosure • Clinicalalgorithms:integratingreproductivehealthinto primaryHIVcare • Educationalbrochures:saferconception,contraception • NodocumentedcasesofmaleÆ femalesexualtransmissionif • PROMEN…onthego… onARTandundetectableviralload • onlyonecaseofmaleÆ malesextransmission www.HIVEonline.org Sturmer Antivir Ther 2008 TDFsafetyinpregnancy PrEPforConception:“PrEPͲception” whenreasonablemindsdiffer? • TheSwiss • JAIDSmetaͲanalysis(17studies;WHOfunded) – PTB<37wRR0.9(0.81Ͳ0.99);<34wRR1.08(0.72Ͳ1.62) – MLHIVonARV;HIVͲRNA<50copies/mlx>3mos – StillbirthRR0.6(0.43Ͳ0.84) – HIVͲRNAinsemenundetectableatbaseline – Neonatalmortality(<14d)RR5.64(1.70Ͳ18.79)drivenbyPROMISE – TDF36hrs and12hoursbeforesex – 1studyclinicallyirrelevantȴ lengthandHCzͲscores – Noȴ maternalAE,SGA,LBW,anomalies,infantAE,infantmortality – n=46pregnancyperattempt – “ThelatestWHOguidelinescontinuetorecommendTDF+FTC(or3TC)+ • 26%(1)Æ 66%(5)Æ 75%(12) EFVasfirstͲlineARTforadults,includingpregnantwomen.” – • BMJOpenmetaͲanalysis(10studies) Noseroconversions oradverseevents – Stillbirth/neonatalmortalityRR4.40(1.75Ͳ11.01) • TheAmericans(SFandNY) – PTB(<34w)RR2.30(1.06 to 4.97) – Retrospectivecohortof“atͲrisk”women(2010Ͳ15) – DrivenbyPROMISE(usedLPV/r;lowerthanexpectedPTBinnonͲTDFarm) – “Theadverseeffectonstillbirthsandneonatalmortalityislikelyan – n=27(5 preconception) overestimate...fullyinformedpregnantwomenlivingwithHIVarelikelyto – Noseroconversions oradverseevents chooseregimensthatdonotincludetenofovir orFTC.” • “AfterfullyconsideringtheresultsofthePROMISEstudy,boththe (PerinatalGL)PanelandtheBHIVAdonotsupportthese Vernazza et al AIDS 2011. Seidman AJOG 2016 recommendations.” Nachega JAIDS2017;SiemieniukBMJOpen2017 AssistedReproductionandHIV • SpermwashingwithIVForIUI=safe • Nocasesoftransmissionwithcurrenttechniques • Expensive(esp IVF) • Limitedavailability – Geographic – Practiceschoosingtonotprovidecare • Thereisnoethicalreasontowithholdfertility servicesatclinicswiththenecessaryresourcesto providecaretoHIVͲ infectedindividualsand coupleswhoarewillingtouserecommended riskͲreducingtherapies.Clinicswithoutsufficient resourcestooffercareshouldassistinreferralto providersequippedtomanagesuchpatients. (ASRM2015) PaulandCaitlinwanttoconceive Ovulation predictor kits theoldfashionedway… • Gettingpregnantsafely – Paulundetectablefor3Ͳ6monthsbeforeattempted conception – CaitlinacandidateforPrEP(necessaryifPaulUD?) – STIcheckforbothofthem – Timedintercourse(condomless sexwhenovulating) • HIVEbrochures:SaferConception,IsPrEPRight forMe?,PrEPduringPregnancyand Breastfeeding,videos PrEPduringPregnancyand Breastfeeding • Appearssafe(somecontroversyasabove) – Breastmilk <<<plasmaconcentration • Duringpregnancyandbreastfeeding – Paul:monthlyviralloads – Caitlin:HIVAg/Ab testingqtri andduringBFat minimum • Viralloadsdependingoncondomuse,hisviralload NumerousmethodstoeliminateHIV transmissionriskwhiletryingtoconceive. Nachego AIDS2017;BrownHepatology 2016;WangCID2013;Ehrhardt CID2015;Fowler PROMISE2014;Palombi2016;Mugo2014 ContraceptiveFailure(1st year) CONTRACEPTION 18% AdaptedfromJ.Trussell Glob.Libr.Women’sMed2011 Efficacydrivenbyfrequencyofmethod HormonalContraception&ART • Permanent:sterilization Increasingefficacy Combohormones/POP Implant • Every10years:CopperTIUD • Every5years:Mirena IUD EFV մ LNGAUCљ58Ͳ83% • Every3years:Nexplanon orSkyla IUD NGMNAUCљ64% ENG љ • Every3Months:DMPA • Monthly:vaginalring RTVͲboosted PIs EEAUCљ19Ͳ48% ? • Weekly:patch NEAUCљ14Ͳ34% • Daily:pill,naturalfamilyplanning(NFP) • Episodic:barriermethods,NFP մ Pregnancyandimplants: 12Ͳ15%EFVvs.0%nonͲEFV(n=570,n=57) PerryAIDS2014;Scarsi CID2016 Cytologic methods • Cytologyalone – ConventionalPap – LiquidͲbasedcytology • Cytology/HPVcoͲtesting SCREENINGFORCERVICAL • NOT recommendedinsettingofHIV – PrimaryHPVtesting DYSPLASIAANDCANCER Conventionalvs.LiquidͲbasedcytology (IamnotendorsingThinPrep.) Conventionalcytology LiquidͲbasedcytology https://cancercervical.wikispaces.com/LIQUID+BASED+ CYTOLOGY+(LBC) http://www.thinprep.com.au/images/diag_typespap_tests.jpg Cytologyreliable(enough) Conventionalvs.LiquidͲbased • HIVEpidemiologyResearch(HER)Study • France,2008Ͳ12,changedtoLBCinSept2009 • 189withHIVvs.95withoutHIV – 277conventional(n=216);268LBC(n=210);allHIV+ st • 2x/yearx6yearfollowͲup(1993Ͳ99):conventionalpap, – Unblinded tomethod,blindedto1 read colposcopy,biopsy – Agreementbtwn 2readers • AnyCIN:14.3%vs.1.2%(p<.01) • Conventional:79abnl,10unsatis;78%(kappa0.69) • Discordantpap/biopsy • LBC:123abnl,2unsatis;84%(kappa0.82) • Baltimore,2000Ͳ01,changedtoLBC(n=358HIV+) – AnyHPV:aOR 3.1(1.0Ͳ9.8) – 209conventional;490LBC – CD4<500:aOR 6.5(1.5Ͳ29.2) – LSIL+:24%conventional,23%LBC • 19HIV+withnormalpapandCIN – ASCͲUS:15%conventional, 9%LBC – 18abnormalpapwithin1yr ofdiscordantresults • f/ubiopsyLSIL+:29%conventional,65%LBC AndersonCID2006 HeardCytopathology2015;Swierczynski Acta Cytol 2004 CervicalCAscreening<30yo Baseline <21y: w/in1yr ofsexualdebut 21Ͳ29:@HIVdx Method CYTOLOGY (conventionalorliquidͲbased) AGEͲBASED HPVcoͲtestingNOTrecommended SCREENINGALGORITHMS Initial Q12months ?Q6 mos x2in1st yr (CIII) FollowͲup 3normal,consecutiveÆ Q3yr Stop Stop ifhysterectomyforbenigndz Continue ifhysterectomyandhx ofCIN2/3, adenoCAͲinͲsitu,cervicalCA CervicalCAscreening30+yo CYTOLOGYALONE CYTOLOGY/HPVcoͲtest Baseline @HIVdx Method Cytology (conventionalorLBC) Cytology/HPV coͲtesting (ifASCͲUSonLBC,±reflex HPV) Initialf/u Q12months IfͲpap/ͲHPVÆ cotest Q3yr ?Q6mos x2in1st yr (CIII) IfͲpap/+HPVÆ cotest @1yr IfASCͲUS/ͲHPVÆ papin6Ͳ If–pap/+HPV 16/18Æ colpo 12morcoͲtestin12m FollowͲ 3normal,consecutiveÆQ3yr If1yrf/u+pap or+HPVÆ colpo up шASCͲUSonrepeatÆ colpo Ifalways–pap/ͲHPVÆ Q3yr Stop NoagecutͲoff(vs.65yr oldamong forHIVͲneg) Stop ifhysterectomyforbenigndz Continue ifhysterectomy(CIN2/3,adenoCIS,cervicalCA) DifferencesbasedonHIV Lessintensivescreeningif CD4>500? • Initiation:noscreening<21yo(HIVͲ)vs.w/in1yr sexdebutif<21yo(HIV+) • Frequency: • KaisernestedcaseͲcontrol – <30yr old:q3yrs (HIVͲ)vs.annualx3(HIV+) • 1996Ͳ2014,incidentCIN2,CIN3,orcervicalcancer – 30+yr old: • 5:1match,20,146cases,100,780controlsͲ(n=115HIV+) • cytologyq3yrs (HIVͲ)vs.annualx3(HIV+) • CIN2+(n=20,146) – • cytology/HPVcoͲtestingq5yrs(HIVͲ)vs.q3yrs(HIV+) HIV:OR2.0 – CD4<200:OR5.7 • Stopping:65yo (HIVͲ)vs.noageͲlimit – CD4200Ͳ499:OR3.0 • Managementofabnormalresults: – NodifferenceCD4500+vs.HIVͲuninfected(OR0.8) – <25yoASCͲUS/+HPV • CIN3+(n=11,275) • cytology12/24m(HIVͲ)vs.colpo (HIV+) – HIV:OR2.3 – ASCͲUS/unknownHPV – CD4<200:OR4.5 • cytology12m(HIVͲ)vs.6/12m(HIV+) – CD4200Ͳ499:OR3.6 – <25yoLSIL – NodifferenceCD4500+vs.HIVͲuninfected(OR0.8) • cytology12/24m(HIVͲ)vs.colpo (HIV+) SilverbergCROI2016 Colposcopy Indicationsforcolposcopyamong womenlivingwithHIV • ASCͲUSwith+reflexHPV – IfHPVunavailable:cytologyat6&12months – IfASCͲUS+onfollowͲupÆ colposcopy • LSIL • ASCͲH • AGC • HSIL http://www.mayoclinic.org/~/media/kcms/gbs/patient%20co nsumer/images/2013/08/26/10/34/my00236_im00350_w7_c olposcopethu_jpg.png Treatment TREATMENTFORCERVICAL DYSPLASIA https://pathologyproject.files.wordpress.com/2012/02/cryoͲ leep.jpg Treatment • CIN2or3 – Satisfactorycolpo,negativeendocervical currettage (ECC) • Ablation(cryotherapy,laser) • Excision(LEEP,laser,coldͲknifecone) – Unsatisfactorycolpo,+ECC • Excision(someonlyofferconetogetcleanmargin) • RecurrentCIN2/3Æ excision • Hysterectomy:considerifrecurrent/persistentCIN3 PREVENTIONOFHPV HPVvaccines • 3FDAͲapprovedHPVvaccines – Bivalent:HPV16,18 – Quadrivalent:HPV6,11,16,18 – 9Ͳvalent:HPV6,11,16,18, 31,33,45,52,58 • Vax with9Ͳvalentifpriorbi/quadvax? • AgecutͲoffforPLHIV?Oct2018:FDAapprovedthrough45yo • AmongthosewithHIV: – Safe – Immunogenic – Ð titers:HIVͲinfection(vs.not);detectableVL:clinical significance? – Seroconversion Ð CD4<200 • Newrecommendationsupto45yorelevantforWLHIV? Kojic CID2014;MoneyVaccine2016;KahnCID2013;WeinbergJID2012 Eosionophilic follicultis • Pruriticurticarialpapulesontheface/neckscalpandchest • CD4under50andwhenstartingARV’sornewregimenasimmune HIV2018 reconstitutionsyndrome • Notadrugreaction TobyMaurer,MD • DONOTSTOPARV’s UniversityofCalifornia,SanFrancisco Treatment • Waititout12Ͳ16weeksuntilimmunesystemstabilizes Antiretrovirals • Itraconazole isthefirstlinedrugͲworksasanantieosinophilic agentͲ WehaveknownthatHIVpsoriasisrespondsbeautifullytoARV’s.This titrateupfrom200qd to400qd.WatchdrugͲdruginteractions pt isanonͲadherentpt whoassoonashisimmunesystemsniffsthe • Permethrinissecondlinedrugwhichweusuallyaddtoitraconazole if ARV’s,responds. notworkingasasingledrug • Prednisoneisoverkillandwouldnotelecttouseitfirstlineinpt with CD4under200 • IndomethicinͲOfuji’s disease : • Mostpeopletake12Ͳ 16weekstorespondtoARV’sre:psoriasis IMMUNCERECONSTITUTIONMOLLUSCUMͲexampleofacute • Intheinterim,canuseacitretin 25qd inflammation • Topicals canbeusedafterARV’sstabilizethept outͲmucheasierto Thepusdoesnotgroworganismsbutiscompletelyfullof handlethepsoriasisanddon’treallyneedmuchmorethanthe inflammatorycells.ThistypeofACUTEINFLAMMATIONistypicalofpts occasionaltopical whostartARV’sunder200withhighviralloads. • WehaveneverhadtogotobiologicsforHIVrelatedpsoriasisͲcan theorizeonmanytothepossiblesideeffects CHRONICINFLAMMATION=Eczemaas PruriticPapular EruptionofHIV example • Thisischronicinflammation.Wehaveknownfordecadesthat • Anotherexampleofchronicinflammation eczemawillalwaysrecurinspiteofwellcontrolledHIVIFthepatient • OftenapresentingsignofHIVinthetropics startedARV’sunder200. • Thoughttobeexaggeratedbugbitereaction • StartARV’sascloselyaspossibletoseroconversionͲdecreasethesize ofthereservoirsoasnottoallowforchronicinflammation • StartARV’sascloseaspossibletoseroconversion Herpessimplex • RespondstoARV’sinthefirst12Ͳ16wks butrecurs • Fewerepisodesinourwelltreatedcohort • Notaspartofresistancetomedsbutagain,asaresultofchronic • ValcyclovirͲ500mgtid inflammationaspersonsinthetropicsstatedARV’sgenerallywith • ?Suppressivedoses?Ͳtreatwhenyouhaveit CD4’sunder200or500 Verrucous HSV HumanPapillomaVirus • UsuallyACVresistant • Stillaburdenoncutaneousskinandgenitalskin • Emergingasaproblemworldwide • ?Vaccinesdecreasingseverityorincidence? • SuppressivedosesofACVusedinrecurrentHSVinfectioninHIVmay • Localdestructivetechniquestoincludeliquidnitrogenand beselectingoutresistantstrains podophylin underocclusion • Treatwithtopicalorinjectablecidofovir • Thinkaboutsquamouscellcancerinthosewartsthatwon’trespond andgetbiggerͲBIOPSY • Cidofovir injections LivinglongerͲchronicactinicdamage Syphilis • Seeingtheravagesofagingskin–actinickeratoses,Basalcellcancers • Manymorphologiesontheskin;hightitersbeingseen andsquamouscellcancers • LotsofsyphilisͲPREP???? • SUNSCREEN100 • Biopsyifindoubt,empirictreatment • HIVincreasestherateofrecurrentsquamouscellcancersoinyour • MonitorforreinfectionorfailedtreatmentͲat1month,3months,6 ptswhohavehad1episodeofsquamouscellcancerͲmonitorclosely( months,12months,18monthsposttreatment q6months)andhavealowthresholdforbiopsy Drugeruptionlikerashthatdoesnot itch=syphilis Kaposis sarcoma • FirstsignofHIVinlowCD4counts • Recurringinptswhoarevirallysuppressed(mayhavehadKSinthe past)ͲblipsofnonͲadherence;aging,steroidinduced • SeeinginMSM’sͲnotHIVinfectedͲ40Ͳ50’s WorkͲup IFHIVNegative • Biopsytoconfirmdiagnosis • Askaboutsymptoms:Pulmonary,GI,Lympehedema • HIVtestonceͲifpositive,startARV’s • Donothing • Askaboutsymptoms;IMAGINGoflimiteduse • Intralesional chemo PULMONARY: coughing,hemoptysis,SOB • Spotradiation GI:tumorinmouththatinterfereswithchewing,GIpain,bloodinstool • TalkabouttriggersͲavoidsystemicsteroids Lymphedema:sustained STARTCHEMOͲliposomaldoxorubicinisfirstlineͲatleast6cycles STARTCOMPRESSIONforlowerlimbs Ihavenodisclosures EnhancingRelationshipͲ CenteredCommunicationfor theHIVProvider ElizabethImbert,MDMPH AssistantProfessor DivisionofHIV,ID,andGlobalMedicine ZuckerbergSanFranciscoGeneral UCSF Objectives Communication: The most common procedure • Identify3stepsofRelationshipͲCenteredCommunicationskillset • Developanactionplantosupportsapplyingtheseskillsinaclinical Howmanypatientinteractionsinahealthcare context provider’scareer? • >200,000 • Lesstraining,practice,andfeedbackthan otherlesscommonprocedures •Computersaddcomplexity Better Outcomes for Patients Relationship-Centered1 Care leads to • Diabetes better outcomes… • Painmanagement • Adherenceto medications • Satisfactionwithcare experiences Safran etal,JFamPract 1998;Stewartetal,JFamPract 2000;Levinsonetal,HealthAffairs2010;Dwamena etal,Cochrane DatabaseSyst Rev2012;Hojat etal,Acad Med2013;Kennedyetal,PatExperienceJ2014 Better Outcomes for Clinicians Overview of Relationship- Centered Interviewing skills and Teams • Engagement • Satisfaction • Workload stress • Medical malpractice Levinsonetal,JAMA1997;Krasneretal,JAMA2009 Step 1: Set the Stage Set the Stage: Greeting Skills: • Welcome/greet the patient and • Build rapport quickly others • Elicit all of the other's agenda items • Integrate interpreter • Negotiate the agenda • Acknowledge delay, if any • Introduce the computer • Identify patient and others by name • Introduce yourself to everyone in the room • Explain your specific role Set the stage: Set the stage: Attend to comfort & minimize communication Elicit ALL agenda items barriers • Ensurereadinessandprivacy • Outpatients average 3-4 • Minimizebarrierstocommunication(sitdown) concerns per visit • Adaptlanguage,pace,postureinrelationtoother • Ensurecomfort • More efficient • Makeasocialcommentoraskanonmedical • 35 vs. 15% doorknob questions question • Main concern often not • Statethetimefortheencounter offered first Marveletal,JAMA1999;Heritageetal,JGIM2007 Set the stage: Set the stage: Elicit all agenda items Negotiate the agenda • “First, let me write down a list of 1. Establish other's priorities: “Of those 4, which is most important to you today?” everything you want to talk about 2. State your concerns: “I’m concerned about your today.” asthma.” 3. Offer a plan: “Can we start with your breathing, • “What else?” until all items then your headache, then your blood pressure exhausted – before addressing first medications? I’ll need a few days to help you with the form.” item • Summarize the entire list Step 2: Elicit & Respond to the Other’s Overview of Relationship-Centered Perspective Interviewing Skills Skills: • Explore the other's function, ideas, fears, and expectations RelationshipͲ Set Set • Demonstrate empathy verbally and Stage Agenda Centered non-verbally Skills • Transition to data-centered portion of encounter Pandora’s Box The Other’s Perspective • Begin with an open-ended request / question • How quickly do you think health care • “Tell me all about …” providers interrupt • Listen attentively and silently patients? • Can use neutral utterances and nonverbal • How long will patients encouragement speak if given the opportunity? • Resist the urge to jump to questions Tools for active listening Skills practice • Pauses Work in dyads. • Echoing You will be in two different roles for 2 minutes each. • Requests for more information 1. Storyteller describes a challenge in a working relationship – with a patient, colleague, • Reflections and summaries supervisor, etc. 2. Interviewer uses pauses, echoing, requests for more information, and reflections/summaries (NOT close-ended questions, advice, or his/her own stories). Need more information? Debrief Elicit the other’s function, ideas, fears, and expectations Forthestorytellerroles: 1. Function “Howhasthisaffectedyourcomfortatwork?” Whatwasitliketotellyourstoryand 2. Ideas experiencereflectivelistening? “Whatareyourideasaboutwhatmightbe Fortheinterviewerroles: causingthis?” 3. Fears Howwasittolistenreflectively? “Whatworriesyouaboutthis?” 4. Expectations “HowcanIbesthelpyoutoday?” Weston,Brown,&Stewart:CanFamPhysician.Jan1989 Explore and Name the Patient’s Elicit & respond: Emotion If not explicit, seek out emotion-- Patients almost always have • “How has this been for you, Symptom emotions accompanying their symptoms/illnesses emotionally?” Personal •Recognize expressed emotion • “How are you doing with all this?” •Nonverbal emotional expression •Emotional cues • Read the emotion on the other's face Emotional •Statements of feeling •Elicit Emotion • “You seem frustrated.” • Ask explicitly • Hypothesize about the patient’s emotion Fortin, Dwamena, Frankel, Smith 2012. Convey empathy nonverbally Express empathy: Make at least one empathic statement • Pause PEARLS: • Touch • Partnership • Facial expression • Emotion • Tone of voice • Apology • Space • Respect • Legitimization • Support Ambady etal,Surgery2002;Riess etal,JGIM2014 PEARLS© statements Empathy enhances efficiency Partnership: Let’s work together on this. Made Missed an empathic opportunity for Emotion: I imagine how upsetting this is for you. statements an empathic Apology: I’m sorry to hear how difficult this is. statement Respect: I give you a lot of credit for getting through this as you have. Internists 17.5 min visits 20 min visits Legitimization: Most people in your position would feel this same way. Surgeons 12.5 min visits 14 min visits Support: I’m going to stick with you through this. Levinsonetal,JAMA2000;Hojatetal,AcadMed2011 Be aware of your own Transition to data-centered reactions part of encounter Self-awareness • Check accuracy with a brief summary • How am I feeling? • Indicate that both content and style of • Does a power differential exist? inquiry will change if patient is ready • Continue with the data-centered portion of Non-judgmental attitude the encounter: remainder of history, exam, • Separate the behavior from the person etc. • Speak as an equal partner Continue connecting and expressing • Focus on strengths compassion! Step 3: Negotiate a shared plan Overview of relationship- centered interviewing skills Skills • Share information Beginning RelationshipͲ RelationshipͲ RelationshipͲ centered centered End Set Set ClinicianͲCentered Physical Centered Educate • Assess understanding Stage Agenda Skills Exam Counsel Skills RelationshipͲ RelationshipͲ Plan centered centered • Summarize & clarify • Close the encounter Share information A Typical Download • Orient and ask permission • Continues with the clinician to begin discussion speaking at length about the diagnosis and treatment plan, • Frame the discussion and what the next steps for the according to the patient’s patient will be, including perspective – ideally medication changes, lifestyle already elicited recommendations, procedural details, consultations, important • Deliver in small, jargon-free things for the patient to know amounts about, maybe ending with asking the patient for any • Allow space for emotion & questions questions … ART Loops Assess Understanding: ARTS • Difference between Askforother'sunderstanding ART dialogue and eflect/respondwitha monologue R • Can be used to elicit: summaryorempathic ART • Patient/family statement preferences, goals Tell/teach ART • Barriers • Ensures simplicity and Seekalignment,solutions maximizes adherence Negotiate a shared plan: Example Develop achievable action plans ASK: What have you heard about asthma? • Tailored to patient's goals, Patient: Oh no. My sister had asthma as a kid. It was awful – she had to go to the ER all the time with my parents to resources, and get treatment. REFLECT: I’m sorry to hear your sister had such severe preferences asthma. TEACH: I don’t think your condition is nearly as serious as • Specific hers. Some people get asthma reactions when they have a virus or allergy, and quickly improve with an inhaler. • Achievable ASK: What is your experience with inhalers? … Summarize and clarify with Summarize and clarify: teach back Teach back, using ART • Teach back leads to Ask the patient to summarize “We’ve covered a lot: can you tell me in your own improved outcomes words what we’ve decided on?” “When you speak with your family member / friend, • Promotes adherence what will you tell them we discussed?” • Allows for collaborative Respond/Reflect Teach additional points, as needed planning Schillingeretal,2003;Schenker etal,2011 Summary: Relationship-Centered Communication Close the encounter Demo and skills practice Step 1: Set the stage Elicit items & negotiate agenda • Further clarify future plans, as Introduce the computer Step 2: necessary Open the conversation • What you / the patient will do Elicit perspectives (FIFE) • What the time of the next communication will be Respond with empathy (PEARLS) • Elicit final questions Step 3: Share information & plans • “What further questions do you have?” Assess understanding with ARTS: • Acknowledge and support Ask with open-ended inquiry, Reflect, • “It is a pleasure to work with you.” Tell/teach, Seek alignment and solutions • “We’ll be here if you need help.” Summarize and clarify: ask for teach back Close the encounter Disclosures Introduction to ARV Drug I have no disclosures Resistance New Clinicians’ Workshop Susa Coffey, MD Division of HIV, ID and Global Medicine ARSQuestion Introduction WhichresistancetestdoyouorderforARTͲnaïve patients? Whatthisis: Fornewclinicians(notexperts) 1.Standardgenotype(RTandPR) Focuson 2.Standardphenotype(RTandPR) •CurrentlyͲusedARVs 3.Genotype+phenotype(RTandPR) •Commonresistancescenarios 4.Integrasephenotype •Genotypetests 5.RT/PR/INgenotype •ApproachestointerpretingRtestresults ProviralDNAgenotype:afewwords Mechanisms of HIV Drug Resistance Mechanisms of HIV Drug Resistance HighrateofHIVreplicationͲ 109 virionsperday MutationsmaydecreasesusceptibilitytoARVs,and Manymutationsandquasispecies causeorcontributetovirologicfailure • RT:errorͲprone,nocopyediting • (afewmutationsmayincrease susceptibility) Insettingofdrugpressurewithviralreplication,selection Somemutationsmayimpairviralfitness ofresistantviruses Somesingle mutationsseverelyimpactcertainARVs • <Ͳ InadequateadherencetoART (eg,M184I/V) • <Ͳ WrongARVs(potency),wrongdoses(druglevels),drugͲ Insomecases,several mutationsareneededtocausea druginteractions,absorptionissues,etc. significantimpact,esp.withNRTIsandPIs(eg,TAMs) • (Corollary:inabsenceofdrugpressure,possible SomeARVsmayretainresidualactivity(eg,3TC/FTC) “disappearance”ofmutations[minoritypopulations]) CrossͲresistancewithinanARVclassiscommon Bottom Line: Assume that once there, always there (archived) When to do Resistance Test: DHHS Recommendations Case: Transmitted Drug Resistance BeforeARTͲͲ atfirstvisit(asclosetothetimeof infectionaspossible) •31yomanwithnewdiagnosisofHIV,chronicity • Resistancemutationsmorelikelytobedetectedearlierin unknown(nopreviousHIVtest) thecourseofHIVinfection • GT:RT,PR;INifconcernfortransmittedINIresistance •CD4:525,HIVRNA:93,000c/mL •GT:RTͲ M41L,K103N;PR– L63P VirologicfailureͲͲ doonfailingARVsorshortlyafter d/c(w/in4weeks) • GTfor1st or2nd ART,addPTif“knownorsuspected complexdrugresistancepattern” • INGTifvirologicfailureonINI SuboptimalvirologicresponseonART Pregnancy DHHSAdult/AdolescentARTGuidelines2018 Prevalence of Transmitted HIV Drug Transmitted HIV Drug Resistance in Resistance in US, 2006-2009 MSM, 2010-2012 Genotypicanalysisofsamplesfromnewlydiagnosedpatientsin CDCNationalHIVSurveillanceSystem(N=12,668) Newly diagnosed MSM patients age 13 in CDC 20 15.6% National HIV Surveillance System, 8 jurisdictions All cases with sequences Cases classified as recent infections (N = 9,629) 16 Cases classified as long-standing infections 12 7.8 8 6.8 4.1 4 0 1 or more 1-class 2-class 3-class NNRTI NRTI PI Transmitted Drug Resistance Mutations (TDRMs) INSTI: case reports, but no significant transmitted resistance—0.2% in one study Ocfemia MCB, et al. CROI 2012. Abstract 730. in N. Carolina Menza TW et al, AIDS 2017. Banez Ocfemia, XXIV HIV Drug Resistance Workshop, 2015. Genotype Test Genotype Test StandardGTexaminesRTandPR M184V First letter: WT ForIN,mustorderspecialtest amino acid Number: codon WithGT,oftenpossibletopredict/anticipate position resistancedependingonthespecificmutations, Second letter: butisnotadirectmeasureofresistance mutant amino acid C, cysteine G, glycine M, methionine S, serine A, alanine H, histidine N, asparagine T, threonine D, aspartate I, isoleucine P, proline V, valine E, glutamate K, lysine Q, glutamine W, tryptophan F, phenyalanine L, leucine R, arginine Y, t y r o s i n e Phenotype Test Phenotype (with GT) Measures inhibition of viral replication by individual ARVs in vitro IC50 = concentration of drug required to inhibit viral replication by 50% Compares patient virus IC50 to that of a reference strain, -> fold-change in IC50 relative to the reference strain FC = IC50 patient IC50 reference Limitations of GT and PT NRTI Resistance Anumberofkeymutationsfor3TC/FTC, Conventionaltestsreliablydetectmutant TDF/TAF,ABC;+numerousothers virusthatcomprisesabout20%ofthe Somesinglemutationsseverelyimpactviral circulatingviralquasispecies replication,butwithothersanaccumulation Maymissminoritypopulations ofmutationsusuallyrequiredforhighͲlevel resistance HIVRNAmustbe>500Ͳ1,000c/mL • (More=worse) DonotassessinteractionofARVs NRTIStrategy: • Knowkeymutations(M184V,K65R,TAMs) • Lookupothers NRTI Resistance: NRTI Resistance: M184I/V K65R Selectedby3TC,FTC(sometimesABC),cause resistanceto3TC,FTC SelectedbyTDF/TAF,ABC,ddI VerycommonͲͲ 3TC/FTChavelowgeneticbarrierto CausesresistancetoTDF/TAF,allotherNRTIsexcept resistance AZT Crossresistance:decreasessusceptibilitytoABC,ddI Increases susceptibilitytoAZT (especiallyifTAMs) Decreasesviralfitness Increases susceptibilitytoTDF/TAF,AZT,d4T • PartiallyrestoresactivityifTAMspresent Decreasesviralfitness NRTI Resistance: TAMs NRTI Resistance: L74V/I ThymidineͲassociatedmutations(TAMs) SelectedbyAZT,d4T DecreasesusceptibilitytoAZT,d4T,TDF/TAF,ABC;toall SelectedbyABCandddI NRTIsifnumerous • (L74VsometimesselectedbyTDF) Crossresistance:increaseswithincreasingnumberof ResistancetoABC andddI TAMs Increases susceptibilitytoTDF/TAF,AZT • (More=worse) 2pathways: • M41L,L210W,T215Y(moreresistance;incl.more impactonTDF) • D67N,K70R,T215F,K219Q/E Case 1: PrEP Failure Case 2: Audience Response WhichARTregimenwouldbemostlikelytobe 31yoMSMonPrEP(TDF/FTC,Truvada),presents effective? toclinicafterabsenceof6months,reportsspotty adherencetohisPrEP,butcontinuestotake. 1.Rilpivirine(RPV)/TAF/FTC(Odefsey) 2.EVG/cobi/TAF/FTC(Genvoya) HIVAb+,HIVRNA65,000c/mL. 3.DTG/ABC/3TC(Tivicay) 4.DRV/r+rilpivirine/TAF/FTC HIVgenotype:RT– K65R,M184V;PR–WT. RT – K65R, M184V NRTIStrategy: PR – WT • Knowkeymutations Bottom Line: need 3 active ARVs, if possible (M184V,K65R,TAMS) (especially if ARVs have low genetic barrier to • Lookupothers resistance). NNRTI Resistance NNRTI Resistance: Important Mutations K103N SeveralsinglemutationsconferhighͲlevelresistance • CommonlyselectedbyEFV tocertainNNRTIs;numerousotherscontributeto • EmergesearlyinVF(lowgeneticbarriertoresistance),commonly resistance transmitted Lowgeneticbarriertoresistance(exceptetravirine, • ResistancetoEFV,NVP ?doravirine) • Byitself,doesnotdecreasesusceptibilitytoETR,RPV,DOR Crossresistanceiscommon Y181I/V/C/F/G/S • SelectedbyNNRTIs • CrossresistancetoallNNRTIs(exceptDOR?) NNRTIStrategy: • Knowseveralkeymutations(K103N,Y181///,E138K E138K [V106]) • SelectedbyRPV • Lookupothers • UsuallyoccurswithM184IorM184V;thisenhancesresistancetoRPV • • Beawareofmutationscoringsystemforetravirine(ETR) ResistancetoRPV,crossresistancetoEFV,ETR • (BecautiousaboutDOR– littleisknown) V106I// • FrequentlyseenafterDORfailure,withothermutations Doravirine Case 2: NNRTI Resistance • Invitro,activeagainstcommon • 53yo manwithVFyearsagoonEFV/TDF/FTC(Atripla), NNRTIresistancemutations nowondolutegravir/ABC/3TC(Triumeq);VL<40c/mLx1 (incl K103N,E138K,Y181C, year.HecomplainsofheadacheandGIsymptomsand G190A) wantstochangeARVs. • Invivo,emergentresistance: • PreviousGT(whileonEFV/TDF/FTC): • TreatmentͲnaïvetrials:V106I, Y188L,H221Y,P225H,F227C • ALSONRTIresistance mutations–eg,M184V,K65R, M41L • Switchstudy(DRIVEͲSHIFT): none • NOclinicaldatainsalvage settings LAIMͲT.CROI2016.Abs506 Case 2: NNRTI Resistance Case 3: 1st ART Failure Couldweuserilpivirine(ordoravirine)+2NRTIs ashisnextARTregimen? 35yowomanonRPV/TAF/FTC(Odefsey).HIV • K103NaloneshouldnotaffectRPV,DOR,orETR RNAsuppressedx2years,thenincreasesto Issues: >5,000c/mLinsettingofseveralmonthsofOTC • AccuracyofGT? PPIuse. • Mutationsmayfadefromviewwithtimeand removalofselectivedrugpressure Genotype: • GTcapturesstrainsthatcomprise>5Ͳ20%ofthe • RTͲ K101E,E138K,Y181C,M184I circulatingviruses • PRͲ nomutations • Oncethere,alwaysthere:“archived”mutations Bottom Line: caution in interpreting GTs – consider what may be hidden from view White, KL. Toronto 2013. Abs 87. Case 3: Audience Response Etravirine Resistance MutationWeightFactor Couldyouuseetravirine(ETR)ordoravirine 1.0 V90IA98G Response by ETR weight (DOR)inhernextregimen? K101E/H 138G/K/Q Genotypic %Responders 179D/T score (DUET trial) G190A 0-2 74.4% 1.Yes– shouldhavefullactivity 1.5 V106IE138A 2.No–noteffectiveafterrilpivirinefailure V179FG190S 2.5-3.5 52% 2.5 L100IK101P 4 38% 3.Ineedmoreinformation Y181CM230L NNRTIStrategy: • Knowseveralkey 3 Y181IY181V mutations(K103N,Y181///, Case: RT - K101E, E138K, E138K[V106]) Y181C, M184I •Lookupothers RT: K101E, E138K, Y181C, M184I •Mutationscoringsystem forETR Bottom line: ETR may not be effective if ETR PR: none •CautionreDOR– littleis score >2. known) Vingerhoets J, et al. AIDS. 2010;24:503-14. Tambuyzer et al JAIDS. 2011. Integrase Inhibitor Resistance Integrase Inhibitor Resistance Raltegravir and elvitegravir have low-ish barriers to resistance INSTI Strategy: • Several possible mutation pathways • Assume cross-resistance between RAL and • Different effects on dolutegravir, ?bictegravir EVG Dolutegravir and bictegravir primary resistance is • Recognize Q148/// (most damaging to DTG) rare, not well understood • Look up all others Order integrase genotype (not phenotype) = special order • (Be very cautious about BIC – little is known) • Important for predicting sensitivity to DTG, BIC u Low et al, Antimicrob Agents Chemother. 2009;53:4275-82 Low et al, Antimicrob Agents Chemother. 2009;53:4275-82 Integrase Inhibitor Resistance Integrase Inhibitor Resistance • Pathway/mutations Resistance Dolutegravir(DTG) Raltegravir Q148H/K/R, G140S/A All INIs (for DTG, Q148 + at Nosignificantreportedemergentmutationsifusedin3Ͳ least one other) drugregimenforinitialtherapy N155H, E92Q RAL, EVG Variousmutationsifusedasmonotherapy Y143R/H/C RAL VariousmutationsifusedafterRALorEVG Q148H/K/R+others,N155H+others,R263K Elvitegravir E92Q EVG, RAL, low level DTG Q148H/K/R, G140S/A All INIs (for DTG, Q148 + at Bictegravir(BIC) least one other) Noreportedemergent mutationsifusedin3Ͳdrugregimen T66I EVG forinitialtherapy Nodataforuseinsalvagetherapy N155H RAL, EVG Low et al, Antimicrob Agents Chemother. 2009;53:4275-82. Kulkarni R et al, CROI 2013, Abs. 587. Case 4: INSTI Resistance Case 4: INSTI Resistance 50yoman,onATV/r/TDF/FTCforyears,switchedto EVG/cobi/TAF/FTC(Genvoya)tosimplifyhisART Willdolutegravirbepotentinhissalvageregimen? VLremained<40c/mLx9months,thenincreasedto7,200 c/mL 1.Yes,theseelvitegravirmutationsdonotaffectDTG GT(incl.integrase)done: 2.No,fullcrossresistanceislikely 3.Possibly,ifweincreasethedoseofDTGto50mgBID INSTI Strategy: •Assume cross-resistance between RAL and EVG •Recognize Q148/// (most IN: G140S, Q148R damaging to DTG) •Look up all others •(Caution re BIC – little is known) Dolutegravir Resistance Bictegravir: in vitro activity against resistant virus VikingͲ3Study:VirologicresponselowestinpatientswithQ148+ш2 secondarymutations VIKINGͲ3:DTG50mgBID+OBRinpatientswithINSTIfailure+2class resistance;hadatleastonefullyactivedruginOBR 79% Bottom Line: 59% • If Q148 + 0 or 1 other 24% mutation, DTG may be effective (with * other active ARVs) ^ • Use BID dosing *Included primary INI-resistance mutations N155H, Y143C/H/R, T66A or E92Q or only historical evidence of resistance ^Secondary mutations from G140A/C/S, E138A/K/T or L74I. Bottom Line: BIC very little Castagna et al, JID 2014:210: 354-362 information on resistance TsiangM,AntimicroAgentsChemother,2016 PI Resistance PI Resistance Primary/Majormutations PIStrategy: • Emergefirst,decreaseantiviraleffect •Beawareof(butdon’tmemorize)listofDRV Secondary/Minormutations resistanceͲassociatedmutations(RAMs) • Emergelater,increasefitnessofstrainswithprimary •Lookupallothers mutationsorfurtherdecreaseantiviraleffect SpecificprimaryandsecondaryPImutations, dependinguponPI **Accumulationofmutationsusuallyrequired forhighͲlevelresistance Crossresistanceiscomplex DRV Resistance-Associated Mutations Case 5: PI (and other) Resistance (DRV-RAMs) 11mutationsassociatedwithresistancetoDRV: 48yoman,reportsthathehasbeenon • V11I,V32I,L33F,I47V,I50V,I54L/M,T74P,L76V,I84V, “everything”inthepast(exceptINSTIs),sometimes L89V withpooradherence. Historicgenotype(s): OnceͲdaily dosingpossibleifno DRVͲRAMS • PRͲͲ L10I,L33F, M36I/M,M46L,I54V,L63S,I64V,V82A (ODINstudy) TwiceͲdaily dosingrecommendedifш1DRVͲ RAM DRVresponsediminishedwithш3DRVͲRAMs De Meyer et al, AIDS Res Hum Retroviruses. 2008;24:379-388 Cahn et al, AIDS. 2011;25:929-39 Case 5: Multiclass Resistance, use Case 5: PI resistance strategies AssessPIresistance: 48yoman,reportsthathehasbeenon“everything”inthe • CheckforDRVresistanceͲmutations past(exceptINSTIs),sometimeswithpooradherence. Historicgenotype(s): V11I, V32I, L33F, I47V, I50V, I54L/M, T74P, L76V, I84V, • RTͲͲ M41L,D67N,L210W,T215Y;V106I,Y181V L89V • PRͲͲ L10I,L33F, M36I/M,M46L,I54V,L63S,I64V,V82A • One DRV-RAM: L33F -> DRV/r likely to be effective but should be given BID Approachingthis:bemethodical,applystrategies • Look up all other mutations • NRTI • NNRTI • PI Case: RT -- M41L, D67N, L210W, T215Y; V106I, Y181V PR -- L10I, L33F, M36I/M, M46L, I54V, L63S, I64V, V82A • (IN) Case 5: Multiclass Resistance (2) Case 5: Multiclass Resistance (3) Historicgenotype(s): ETRMutationWeight Historicgenotype(s): • RTͲͲ M41L,D67N,L210W,T215Y;V106I,Y181V Factor • PRͲͲ L10I,L33F,M36I/M,M46L,I54V,L63S,I64V,V82A 1.0 V90I • RTͲͲ M41L,D67N,L210W,T215Y;V106I,Y181V A98G • PRͲͲ L10I,L33F, M36I/M,M46L,I54V,L63S,I64V,V82A K101E/H 138G/K/Q • AssessNNRTIresistance: 179D/T G190A AssessNRTIresistance: • 2NNRTImutations(incl.Y181) • ETRscore: 1.5 V106I • 4mutations(allTAMs)Ͳ affectTDF/TAF,ABC E138A • 4.5 V179F • Anythingmissing? • DOR:littleknown(caution:V106I) G190S • NoM184V/I– why??? 2.5 L100I NNRTIStrategy: K101P NRTIStrategy: •Knowseveralkeymutations(K103N, Y181C • Knowkeymutations Y181///,E138K[V106]) M230L (M184V,K65R,TAMS) •Lookupothers 3 Y181I • • Lookupothers MutationscoringsystemforETR Y181V •CautionreDOR– littleisknown) Case 5: Multiclass Resistance (5): Case 5: Multiclass Resistance (4) “Look up other mutations” Historicgenotype(s): • RTͲͲ M41L,D67N,L210W,T215Y;V106I,Y181V • PRͲͲ L10I,L33F,M36I/M,M46L,I54V,L63S,I64V,V82A • AssessPIresistance: • 8PImutations(1DRVmutation) PIStrategy: • BeawareoflistofDRV Case:RTͲͲ M41L,D67N,210W, Conclusion: likely resistance to T215Y;V106I,Y181V resistanceͲassociated all NNRTIs (??DOR), and to all PIs mutations(RAMs) PRͲͲ L10I,L33F,M36I/M,M46L, I54V,L63S,I64V,V82A except DRV – use BID • Lookupallothers Stanford HIV Drug Resistance Database http://hivdb.stanford.edu Case 5, continued What ARVs should we use in the next regimen? • Summary: • 3Ͳclassresistance: Integraseinhibitor? • NRTI:4mutations(TAMs): M41L,D67N,210W,T215Y • CrossresistancetoTDF,ABC Darunavir/r? • NoM184V/Ibutwewillassumeitisthere NNRTI? • 3TC/FTCresistance • NNRTI:2mutations:V106I,Y181V NRTIs? • LikelyresistancetoETR,DOR CCR5antagonist? • PI:8mutations(1DRVRAM) • Integraseinhibitors:neverexposed • WhatARVsshouldweuseinthenextregimen? Proviral DNA Genotype Proviral DNA Genotype Background: AmplifiescellͲassociated HIVͲ1proviralDNA StandardresistancetestrequiresplasmaHIVRNAof frominfectedcells(PBMCs) >500Ͳ1,000c/mL •Whole blood samples ManypatientscurrentlyonARTwithVL<40mayhave resistancefrompreviousregimensbuthavenoavailable AnalyzesHIVͲ1polymeraseregionbynew resistanceteststoguideARTchanges(eg,simplification) generationsequencingtechnology CanwedoresistancetestingonarchivedHIV? Case6 ProviralDNAGenotyping–HowAccurate? • 55yo manHIV+1993,onARTxyears • PreviousARThistoryunclear– remembersAZT,D4T,3TC,ABC, DDI,EFV,NVP,IDV,SQV,LVPͲr • TransferredtothiscliniconATVͲr+AZT+TDF/FTC,HIVRNA= ND • ChangedtoATVͲr+RAL+TDF/FTCx5years,HIVRNA=ND • Proviral DNAGT: • RT:M184V,K103K/N • IN:None • PR:L90L/M • ChangedtoEVG/cobi/TAF/FTC+DRV Toma J. ICAAC. 2015 DNA Genotype Summary Doresistancetestsattimeofdiagnosisandifvirologic Bottom Line: failure+suspectedresistance(usuallyGT) • Can be helpful if shows resistance Resistance:oncetherealwaysthere(archived) mutations. Bewareofwhatyoudon’tsee(minoritypopulations) Lookatoldresistancereports,treatmenthistory • May miss some or all existing resistance mutations: caution re Readresistancereportsmethodically CautionreARVswithscantydata(eg,BIC,DOR) negative results **Seekexpertadvice** • No clinical data Goaloftreatment:suppressedHIVRNAforall Resources StanfordHIVDrugResistanceDatabase • http://hivdb.stanford.edu IASͲUSAHIVDrugResistanceMutationsFigures andUserNotes • https://www.iasusa.org ClinicianConsultationCenter • (800)933Ͳ3413 Monday–Friday,9a.m.–8p.m.EST (Free!) ŝƐĐůŽƐƵƌĞƐ ,KDYHUHFHLYHGJUDQWIXQGLQJIURPWKH1DWLRQDO,QVWLWXWHVRI+HDOWKDQGWKH KƉƉŽƌƚƵŶŝƐƚŝĐ/ŶĨĞĐƚŝŽŶƐĂŶĚ *LOHDG5HVHDUFK6FKRODUV3URJUDPLQ+,9 /ŵŵƵŶĞZĞĐŽŶƐƚŝƚƵƚŝŽŶ /ŶĨůĂŵŵĂƚŽƌLJ^LJŶĚƌŽŵĞ &DWKHULQH.RVV0' $VVLVWDQW3URIHVVRU 'LYLVLRQRI+,9,QIHFWLRXV'LVHDVHVDQG*OREDO0HGLFLQH 'HFHPEHU KďũĞĐƚŝǀĞƐ ϰĐŽƵŶƚĐŽƌƌĞůĂƚĞƐǁŝƚŚƌŝƐŬŽĨƐƉĞĐŝĨŝĐK/ƐŝŶ ƵŶƚƌĞĂƚĞĚ,/sĚŝƐĞĂƐĞ ŝĂŐŶŽƐĞĂŶĚŵĂŶĂŐĞĐŽŵŵŽŶŽƉƉŽƌƚƵŶŝƐƚŝĐŝŶĨĞĐƚŝŽŶƐ;K/ƐͿŝŶ,/s TB VZV/Zoster ϲϬϬ 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^dKWĂŶĚĚŽŶŽƚƌĞͲĐŚĂůůĞŶŐĞŝĨƉƚ WƌĞĚŶŝƐŽŶĞϮϬŵŐĚĂŝůLJdžϭϭĚĂLJƐ ŚĂƐ^ƚĞǀĞŶƐͲ:ŽŚŶƐŽŶƐLJŶĚƌŽŵĞŽƌ ƚŽdžŝĐĞƉŝĚĞƌŵĂůŶĞĐƌŽůLJƐŝƐ DŝůĚ WƌĞĨĞƌƌĞĚ dDWн^Dy;ǁĞŝŐŚƚͲďĂƐĞĚͿ ͲĂŐƌĂĚфϯϬ WĂKϮtϳϬ ͲĂŐƌĂĚфϯϱ ^ƵƌǀŝǀĂů ͲĂŐƌĂĚхϯϬ DŽŶƚĂŶĞƌĞƚĂů͘ŶŶ/Ŷƚ DĞĚϭϵϵϬ͘ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘E/,Ͳh džƉĞƌƚWĂŶĞůĨŽƌŽƌƚŝĐŽƐƚĞƌŽŝĚƐĂƐĚũƵŶĐƚŝǀĞdŚĞƌĂƉLJĨŽƌWW͘E :D ϭϵϵϬ͘ ƌĞŶŶĞƌĞƚĂů͘ŵZĞǀZĞƐƉŝƌŝƐϭϵϴϳ͘ĞůͲ^ĂĚƌĂŶĚ^ŝŵďĞƌŬŽĨĨ͘ŵZĞǀZĞƐƉŝƌ ŝƐϭϵϴϴ͘ _>IRRWHUWH[WKHUH@ WW͗dƌĞĂƚŵĞŶƚ WW͗dƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ ŝƐĞĂƐĞ WƌĞĨĞƌĞŶĐĞ ZĞŐŝŵĞŶ WŽƚĞŶƚŝĂůƚŽdžŝĐŝƚŝĞƐ ƐĞǀĞƌŝƚLJ ;ϮϭĚĂLJƐƚŚĞŶƐƚĂƌƚƐĞĐŽŶĚĂƌLJƉƉdžͿ ĚǀĞƌƐĞĞĨĨĞĐƚƐĂƌĞĐŽŵŵŽŶ DŽĚĞƌĂƚĞƚŽ WƌĞĨĞƌƌĞĚ dDWн^Dy;ǁĞŝŐŚƚͲďĂƐĞĚͿ Æ ZĂƐŚ͕ĨĞǀĞƌ͕ůĞƵŬŽƉĞŶŝĂ͕ /ĨƉĂƚŝĞŶƚŶŽƚŝŵƉƌŽǀŝŶŐĂĨƚĞƌϯĚĂLJƐ͕ŝƐƚŚŝƐƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ͍ ƐĞǀĞƌĞ ĚũƵƐƚĚŽƐĞĨŽƌƌĞŶĂůĨƵŶĐƚŝŽŶ ƚŚƌŽŵďŽĐLJƚŽƉĞŶŝĂ͕ĂnjŽƚĞŵŝĂ͕ /sÆ WKĂĨƚĞƌĐůŝŶŝĐĂůŝŵƉƌŽǀĞŵĞŶƚ ŚĞƉĂƚŝƚŝƐ͕ŚLJƉĞƌŬĂůĞŵŝĂ 'ĞŶĞƌĂůůLJŶŽ͖ĞĂƌůLJǁŽƌƐĞŶŝŶŐĂƚϯͲϱĚĂLJƐŝƐĐŽŵŵŽŶ WĂKϮфϳϬ dƌLJƚŽ͞ƚƌĞĂƚƚŚƌŽƵŐŚ͟ƌĞĂĐƚŝŽŶƐŝĨ ƉŽƐƐŝďůĞ t tĂŝƚĂƚůĞĂƐƚϰͲϴĚĂLJƐ ĨŽƌĂĐůŝŶŝĐĂůƌĞƐƉŽŶƐĞďĞĨŽƌĞƐǁŝƚĐŚŝŶŐƚŚĞƌĂƉLJĨŽƌ ͲĂŐƌĂĚ ϯϱ ^ƚĞƌŽŝĚƐ ǁŝƚŚŝŶϳϮŚŽƵƌƐ ĞƐĞŶƐŝƚŝnjĂƚŝŽŶƉƌŽƚŽĐŽůƐĂǀĂŝůĂďůĞ WƌĞĚŶŝƐŽŶĞϰϬŵŐ/džϱĚĂLJƐ ĨŽƌƉĂƚŝĞŶƚƐǁŝƚŚĂůůĞƌŐLJ ĐůŝŶŝĐĂůĨĂŝůƵƌĞ WƌĞĚŶŝƐŽŶĞϰϬŵŐĚĂŝůLJdžϱĚĂLJƐ ^dKWĂŶĚĚŽŶŽƚƌĞͲĐŚĂůůĞŶŐĞŝĨƉƚ WƌĞĚŶŝƐŽŶĞϮϬŵŐĚĂŝůLJdžϭϭĚĂLJƐ ŚĂƐ^ƚĞǀĞŶƐͲ:ŽŚŶƐŽŶƐLJŶĚƌŽŵĞŽƌ ƚŽdžŝĐĞƉŝĚĞƌŵĂůŶĞĐƌŽůLJƐŝƐ ůƚĞƌŶĂƚŝǀĞηϭ ůŝŶĚĂŵLJĐŝŶнƉƌŝŵĂƋƵŝŶĞнƐƚĞƌŽŝĚƐ Æ ŶĞŵŝĂ͕ƌĂƐŚ͕ĨĞǀĞƌ͕ĚŝĂƌƌŚĞĂ ǀĂůƵĂƚĞĨŽƌĐŽŶĐƵƌƌĞŶƚŝŶĨĞĐƚŝŽŶƐ ĂƐĂĐĂƵƐĞĨŽƌĐůŝŶŝĐĂůĨĂŝůƵƌĞʹĐŽŶƐŝĚĞƌ ;ƌdž ĨĂŝůƵƌĞͬ ŚĞĐŬ'ϲW ƌĞƉĞĂƚďƌŽŶĐŚ ƚŽdžŝĐŝƚLJͿ ůƚĞƌŶĂƚŝǀĞηϮ WĞŶƚĂŵŝĚŝŶĞ/sнƐƚĞƌŽŝĚƐ Æ /ƌƌĞǀĞƌƐŝďůĞƌĞŶĂůĂŶĚƉĂŶĐƌĞĂƚŝĐ ,ŝƐƚŽƌŝĐĂůůLJƉƌĞĨĞƌƌĞĚ͘,ŝŐŚĞƌŵŽƌƚĂůŝƚLJ ŝƐůĞƚĐĞůůƚŽdžŝĐŝƚŝĞƐ͕ĂƌƌŚLJƚŚŵŝĂƐ͕ ŝŶƌĞƚƌŽƐƉĞĐƚŝǀĞƐƚƵĚŝĞƐ͘tĞĂǀŽŝĚ͘ ŚLJƉŽŐůLJĐĞŵŝĂ͕ŚLJƉŽƚĞŶƐŝŽŶ DŝůĚ WƌĞĨĞƌƌĞĚ dDWн^Dy WĂKϮtϳϬ ůƚĞƌŶĂƚŝǀĞ ůŝŶĚĂŵLJĐŝŶнƉƌŝŵĂƋƵŝŶĞ͘ŚĞĐŬ'ϲW Æ ŶĞŵŝĂ͕ƌĂƐŚ͕ĨĞǀĞƌ͕ĚŝĂƌƌŚĞĂ ͲĂŐƌĂĚфϯϱ ĂƉƐŽŶĞнdDW͘ŚĞĐŬ'ϲW Æ ZĂƐŚ͕ĨĞǀĞƌ ƚŽǀĂƋƵŽŶĞ/ǁŝƚŚĨŽŽĚ Æ ,͕ŶĂƵƐĞĂ͕ĚŝĂƌƌŚĞĂ͕ƌĂƐŚ͕>&dƐ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘E/,Ͳh džƉĞƌƚWĂŶĞůĨŽƌŽƌƚŝĐŽƐƚĞƌŽŝĚƐĂƐĚũƵŶĐƚŝǀĞdŚĞƌĂƉLJĨŽƌWW͕E :D ϭϵϵϬ͘ ĂƐĞϮ ĂƐĞϮĐŽŶƚŝŶƵĞĚ ϰϬLJŽ DǁŝƚŚ,/s;ϰϰϮϬĂŶĚs>фϰϬŽŶd'н&dͬd&ϭ͘ϱLJĞĂƌƐĂŐŽͿ͕ůŽƐƚ dƐŚŽǁƐďƵůŬLJŶĞĐƌŽƚŝĐŶŽĚĞƐŝŶŵĞĚŝĂƐƚŝŶƵŵĂŶĚƌĞƚƌŽƉĞƌŝƚŽŶĞƵŵ͘ ƚŽĨŽůůŽǁͲƵƉ͘ WƌĞƐĞŶƚƐǁŝƚŚƐĞǀĞƌĂůǁĞĞŬƐŽĨƉƌŽŐƌĞƐƐŝǀĞƐLJŵƉƚŽŵƐ͗ĚŝĨĨƵƐĞĂďĚŽŵŝŶĂůƉĂŝŶ͕ ĨĞǀĞƌ͕ĚŝĂƌƌŚĞĂ;ϭϬdžƉĞƌĚĂLJͿ͕ĂŶĚĐĂĐŚĞdžŝĂ͘ WD,͗ ,/sĚŝĂŐŶŽƐĞĚϮLJĞĂƌƐĂŐŽ͕ϰϯϴϬ͕s>ϴϬ< ^ŽĐŝĂů,ŝƐƚŽƌLJ͗ /ŵŵŝŐƌĂƚĞĚƚŽĨƌŽŵDĞdžŝĐŽϮϬLJĞĂƌƐĂŐŽ DĂƌŐŝŶĂůůLJŚŽƵƐĞĚ >ĂďƐ͗ ,Őďϳ͕ŶŽƌŵĂů>&dƐ͕ƌϭ͘Ϭ ϰϰϴ;ϲйͿ͕s>ƉĞŶĚŝŶŐ _>IRRWHUWH[WKHUH@ dĐŚĞƐƚ tŚĂƚŝƐƚŚĞŵŽƐƚůŝŬĞůLJĚŝĂŐŶŽƐŝƐ͍ EƵŵĞƌŽƵƐƉƵůŵŽŶĂƌLJŶŽĚƵůĞƐŝŶh>ĂŶĚZD>͕ůĂƌŐĞƐƚϭ͘ϴĐŵ ϭ͘ LJƚŽŵĞŐĂůŽǀŝƌƵƐ;DsͿ Ϯ͘ DLJĐŽďĂĐƚĞƌŝƵŵƚƵďĞƌĐƵůŽƐŝƐ;dͿ ϯ͘ DLJĐŽďĂĐƚĞƌŝƵŵĂǀŝƵŵĐŽŵƉůĞdž ;DͿ ϰ͘ >LJŵƉŚŽŵĂ ^LJŶĚƌŽŵŝĐĚŝĨĨĞƌĞŶƚŝĂůĐĂŶŚĞůƉƉƌĞĚŝĐƚƉĂƚŚŽŐĞŶƐŝŶƉĂƚŝĞŶƚƐ ĂƐĞϮĐŽŶƚŝŶƵĞĚ ǁŝƚŚϰфϱϬ ^ƚŽŽůĐƵůƚƵƌĞƐĂŶĚKΘWͲ 'ŝĂƌĚŝĂŐƉŽƐŝƚŝǀĞ ^ŚŽƌƚdž͗ ^ŚŽƌƚdž͗ /^нĨĞǀĞƌнǁĂƐƚŝŶŐнůLJŵƉŚĂĚĞŶŽƉĂƚŚLJ /^нƉƵůŵŽŶĂƌLJŶŽĚƵůĞƐ ^ĞƌƵŵƌLJƉƚŽĐŽĐĐĂůŐ;ƌŐͿͲ ŶĞŐĂƚŝǀĞ ŝƐƐĞŵŝŶĂƚĞĚD dƵďĞƌĐƵůŽƐŝƐ hƌŝŶĞ,ŝƐƚŽƉůĂƐŵĂŐͲ ŶĞŐĂƚŝǀĞ dƵďĞƌĐƵůŽƐŝƐ &ƵŶŐĂů;ƌLJƉƚŽ͕ŽĐĐŝĚŝŽŝĚŽŵLJĐŽƐŝƐͿ ŝƐƐĞŵŝŶĂƚĞĚĨƵŶŐĂů;,ŝƐƚŽ͕ƌLJƉƚŽͿ <ĂƉŽƐŝƐĂƌĐŽŵĂ ^ƉƵƚƵŵ&ƐŵĞĂƌdžϯͲ ŶĞŐĂƚŝǀĞ >LJŵƉŚŽŵĂ >LJŵƉŚŽŵĂ &ďůŽŽĚĐdžĚƌĂǁŶ͖ƐƚĂƌƚĞĚŽŶĞŵƉŝƌŝĐƚƌĞĂƚŵĞŶƚĨŽƌD ^ŚŽƌƚdž͗ /^нƉƌŽůŽŶŐĞĚĚŝĂƌƌŚĞĂ WĂƌĂƐŝƚĞƐ ;ĐƌLJƉƚŽƐƉŽƌŝĚŝƵŵ͕ŵŝĐƌŽƐƉŽƌŝĚŝƵŵͿ ZĞƐƚĂƌƚĞĚZd͗ŽůƵƚĞŐƌĂǀŝƌн&dͬd& ĂĐƚĞƌŝĂů ;^ĂůŵŽŶĞůůĂ͕^ŚŝŐĞůůĂͿ͕ŵLJĐŽďĂĐƚĞƌŝĂů ;D͖dŝůĞŝƚŝƐͿ sŝƌĂů͗DsĐŽůŝƚŝƐ &ƵŶŐĂů͗,ŝƐƚŽƉůĂƐŵŽƐŝƐ KƚŚĞƌ͗,/sĞŶƚĞƌŽƉĂƚŚLJ͕DĂůŝŐŶĂŶĐLJ͗ůLJŵƉŚŽŵĂ͕<ĂƉŽƐŝƐĂƌĐŽŵĂ;,,sϴͿ _>IRRWHUWH[WKHUH@ tŚĞŶƚŽƐƵƐƉĞĐƚDLJĐŽďĂĐƚĞƌŝƵŵǀŝƵŵĐŽŵƉůĞdž DdƌĞĂƚŵĞŶƚ͗ƚůĞĂƐƚƚǁŽĚƌƵŐƐ ƌƵŐϭ͗DĂĐƌŽůŝĚĞ ƌƵŐϮ нͬͲ ƌƵŐϯ нͬͲ ƌƵŐϰ ůŝŶŝĐĂů͗ &ĞǀĞƌ͕ǁĞŝŐŚƚůŽƐƐ͕нͬͲ ĚŝĂƌƌŚĞĂ͕нͬͲ ĂďĚ ƉĂŝŶ ůĂƌŝƚŚƌŽŵLJĐŝŶ ƚŚĂŵďƵƚŽů ZŝĨĂďƵƚŝŶ DŽdžŝĨůŽdžĂĐŝŶ ;ŵŽƌĞĚĂƚĂͿ >ĞǀŽĨůŽdžĂĐŝŶ >ĂďŽƌĂƚŽƌLJ͗ ŝƉƌŽĨůŽdžĂĐŝŶ ϰфϱϬ Kƌ ůĞǀĂƚĞĚĂůŬĂůŝŶĞƉŚŽƐƉŚĂƚĂƐĞ ŵŝŬĂĐŝŶ ŶĞŵŝĂͬƉĂŶĐLJƚŽƉĞŶŝĂĚƵĞƚŽďŽŶĞŵĂƌƌŽǁ njŝƚŚƌŽŵLJĐŝŶ ^ƚƌĞƉƚŽŵLJĐŝŶ ŝŶĨŝůƚƌĂƚŝŽŶ ;ďĞƚƚĞƌƚŽůĞƌĂƚĞĚ͕ĨĞǁĞƌ ĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐͿ ŝĂŐŶŽƐƚŝĐƐ͗ &ďůŽŽĚĐƵůƚƵƌĞƐ;ΎĚƌĂǁƉƌŝŽƌƚŽĂnjŝƚŚƌŽŵLJĐŝŶͿ ŽŶƐŝĚĞƌĂϯƌĚ ĚƌƵŐŝĨŚŝŐŚďƵƌĚĞŶŽĨĚŝƐĞĂƐĞŽƌƉƚ ŶŽƚŽŶZd ^ĞŶƐŝƚŝǀŝƚLJϵϭйĨŽƌϭ&ďůŽŽĚĐƵůƚƵƌĞƐ ^ĞŶƐŝƚŝǀŝƚLJϵϴйĨŽƌϮ&ďůŽŽĚĐƵůƚƵƌĞƐ DŽŶŝƚŽƌŝŶŐ͗ dĂďĚŽŵĞŶŽĨƚĞŶƌĞǀĞĂůƐŚĞƉĂƚŽƐƉůĞŶŽŵĞŐĂůLJ ZĞƉĞĂƚ&ďůŽŽĚĐdžĂƚϰǁĞĞŬƐ ĂŶĚŝŶƚƌĂďĚŽŵŝŶĂůůLJŵƉŚĂĚĞŶŽƉĂƚŚLJ ŽŶƐŝĚĞƌƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞŝĨ DĂLJŶĞĞĚƚŝƐƐƵĞďŝŽƉƐLJ;Ğ͘Ő͘ůLJŵƉŚŶŽĚĞͿ ŶŽŝŵƉƌŽǀĞŵĞŶƚŝŶƐdž ƐƚŝůůďĂĐƚĞƌĞŵŝĐ ĂĨƚĞƌϰǁĞĞŬƐŽĨƌdž ƵƌĂƚŝŽŶ͗ĂƚůĞĂƐƚϭLJĞĂƌĂŶĚϰхϱϬ <ĂƌĂŬŽƵƐŝƐ WĞƚĂů͘>ĂŶĐĞƚ/ŶĨĞĐƚŝƐϮϬϬϰ͘,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘ ĞŶƐŽŶĂŶĚ ůůŶĞƌ͘/ ϭϵϵϯ͘ tĂƌĚϴϲDĂŶĂŐĞŵĞŶƚZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ͕,/s/Ŷ^ŝƚĞ͘ WƌŝŵĂƌLJDƉƌŽƉŚLJůĂdžŝƐ͗ ǀŽůǀŝŶŐŐƵŝĚĞůŝŶĞƐ WƌŽƉŚLJůĂdžŝƐŽĨK/Ɛ͗dŚĞďĂƐŝĐƐ K/ /ŶĚŝĐĂƚŝŽŶƐ ĨŽƌ ZĞŐŝŵĞŶŽĨĐŚŽŝĐĞĂŶĚ tŚĞŶƚŽƐƚŽƉ ŽŶƐŝĚĞƌĂƚŝŽŶƐĨŽƌ ƉƌŝŵĂƌLJƉƉdž ĂůƚĞƌŶĂƚŝǀĞƌĞŐŝŵĞŶƐ ƉƌŝŵĂƌLJƉƉdž ƐĞĐŽŶĚĂƌLJƉƉdžͬ ;ŝŶƉƚƐŽŶZdͿ ĐŚƌŽŶŝĐŵĂŝŶƚĞŶĂŶĐĞƌdž WW ϰфϮϬϬ Žƌ dDWͲ^Dyϭ^ĚĂŝůLJ ϰхϮϬϬdž хϯ ŵŽ ^ƚĂƌƚƐĞĐŽŶĚĂƌLJƉƉdž ĂĨƚĞƌ ϰфϭϰй dDWͲ^Dyϭ^^ĚĂŝůLJ ĂŶĚs>E ĐŽŵƉůĞƚŝŶŐWWƌdž ϯϲϵƉĂƚŝĞŶƚƐǁŝƚŚϰфϱϬŽŶZd ŝŶ,/sKƵƚƉĂƚŝĞŶƚ^ƚƵĚLJ;,KW^Ϳ͕ϭϵϵϲͲϮϬϬϳϭ dDWͲ^Dyϭ^ϯdžͬǁŬ ϭ͕Ϯ /ĨƉƚ ŚĂƐWWĂƚϰхϮϬϬŽŶ ĂƉƐŽŶĞ KZ Zd͕ĐŽŶƐŝĚĞƌůŝĨĞͲůŽŶŐ ϭϭŝŶĐŝĚĞŶƚDŝŶĨĞĐƚŝŽŶƐ Ϯ ĞƌŽƐŽůŝnjĞĚƉĞŶƚĂŵŝĚŝŶĞ ƐĞĐŽŶĚĂƌLJƉƉdž ϬŝŶƉĂƚŝĞŶƚƐǁŝƚŚ,/sZEфϭϬϬϬĐͬŵůƌĞŐĂƌĚůĞƐƐŽĨǁŚĞƚŚĞƌŽŶƉƉdž ƚŽǀĂƋƵŽŶĞǁŝƚŚŵĞĂů ϰхϭϬϬĂŶĚ s>EdžϯͲϲŵŽŶƚŚƐ dŽdžŽƉůĂƐŵĂ ϰфϭϬϬ dDWͲ^Dyϭ^ĚĂŝůLJ ϰхϮϬϬdž хϯ ŵŽ ĨƚĞƌŝŶŝƚŝĂůdŽdžŽ ƌdž͕ƐǁŝƚĐŚ ,,^ŐƵŝĚĞůŝŶĞƐϮ ƌĞĐŽŵŵĞŶĚƉƉdž ƵŶƚŝůϰхϭϬϬ;ůĂƐƚƵƉĚĂƚĞĚϮϬϭϯ͖ƵƉĚĂƚĞŝŶƉƌŽŐƌĞƐƐͿ ŐŽŶĚŝŝ ĂŶĚdŽdžŽ /Ő'н dDWͲ^Dyϭ^ϯdžͬǁŬ ĂŶĚs>E ƚŽĐŚƌŽŶŝĐŵĂŝŶƚĞŶĂŶĐĞƌdž ƵŶƚŝůϰхϮϬϬdžхϲŵŽ͘ ϯ ĂƉƐŽŶĞнƉLJƌŝŵĞƚŚĂŵŝŶĞ /^Ͳh^ŐƵŝĚĞůŝŶĞƐ ŶŽůŽŶŐĞƌƌĞĐŽŵŵĞŶĚƉƌŝŵĂƌLJDƉƉdž ϭ ;WLJƌŝŵĞƚŚĂŵŝŶĞн нůĞƵĐŽǀŽƌŝŶ KZ ƐƵůĨĂĚŝĂnjŝŶĞнůĞƵĐŽǀŽƌŝŶ KƵƌƉƌĂĐƚŝĐĞĂƚƵĐŬĞƌďĞƌŐ^ĂŶ&ƌĂŶĐŝƐĐŽ'ĞŶĞƌĂů,ŽƐƉŝƚĂů͗ϰ ƚŽǀĂƋƵŽŶĞǁŝƚŚŵĞĂů ƉƌĞĨĞƌƌĞĚͿ ϰхϭϬϬĂŶĚ /ĨƉĂƚŝĞŶƚŚĂƐƐŝŐŶƐͬƐLJŵƉƚŽŵƐ;ĨĞǀĞƌ͕ǁĞŝŐŚƚůŽƐƐ͕>͕,^D͕ĚŝĂƌƌŚĞĂͿŽĨĚD s>EdžϯͲϲŵŽŶƚŚƐ ^ƚĂƌƚĞŵƉŝƌŝĐ DƚƌĞĂƚŵĞŶƚнZd D ϰфϱϬ ĂŶĚ njŝƚŚƌŽ ϭϮϬϬŵŐǁĞĞŬůLJ ϰхϭϬϬdž хϯ ŵŽ ŽŶƚŝŶƵĞƚƌĞĂƚŵĞŶƚĨŽƌ ŶŽĞǀŝĚĞŶĐĞ njŝƚŚƌŽ ϲϬϬŵŐϮdžͬǁŬ ĂŶĚs>Eϰ ĚD ƌĞŐŝŵĞŶĨŽƌt ϭϮŵŽƐ DŽŶŽƚŚĞƌĂƉLJĨŽƌDͲ ŚŝŐŚƌĂƚĞŽĨŵĂĐƌŽůŝĚĞƌĞƐŝƐƚĂŶĐĞ͖D/Z/^ĐĂŶďĞƐĞǀĞƌĞ ŽĨĚD ZŝĨĂďƵƚŝŶϯϬϬŵŐĚĂŝůLJϯ ĂŶĚƵŶƚŝůϰхϱϬĂŶĚŶŽ ƐŝŐŶƐŽĨĚD /ĨƉĂƚŝĞŶƚĚŽĞƐŶŽƚŚĂǀĞƐŝŐŶƐͬƐLJŵƉƚŽŵƐŽĨĚD KZ ^ƚĂƌƚƉƌŝŵĂƌLJƉƌŽƉŚLJůĂdžŝƐнZd s>фϭϬϬϬƌĞŐĂƌĚůĞƐƐ ŝƐĐŽŶƚŝŶƵĞƉƉdž ǁŚĞŶs>фϭϬϬϬƌĞŐĂƌĚůĞƐƐŽĨϰ ŽĨϰϱ ϭ͘ zĂŶŐĐŽ 'ĞƚĂů͘/^WĂƚĂƌĞ^dƐϮϬϭϰ͘Ϯ͘,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘ϯ͘^ĂĂŐ DĞƚĂů͘:D ϮϬϭϴ͘ 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DsƐĞƌŽůŽŐLJ͕ƐĞƌƵŵWZ͕ĂŶĚ ϰǁĞŶƚĨƌŽŵϰϲͲхϴϱ͕ĂŶĚs>ϮϬϬ<Ͳхϭϴ<͘ ĞƌŽƐŝŽŶŽƌƵůĐĞƌƐǁŝƚŚDsŝŶĐůƵƐŝŽŶƐŽŶƉĂƚŚ ǀŝƌĂůĐƵůƚƵƌĞŶŽƚ ŚĞůƉĨƵů WĂƚŝĞŶƚƐǁŝƚŚDs'/ŽƌŶĞƵƌŽůŽŐŝĐ EĞƵƌŽ͗ĞŶĐĞƉŚĂůŝƚŝƐ͕ƉŽůLJƌĂĚŝĐƵůŝƚŝƐ͕ ĚŝƐĞĂƐĞƐŚŽƵůĚŚĂǀĞĚŝůĂƚĞĚĞLJĞ >ĂďƐĂƌĞŽƚŚĞƌǁŝƐĞƵŶĐŚĂŶŐĞĚ͘ ŵLJĞůŽƉĂƚŚLJ ĞdžĂŵ ůŝŶŝĐĂůĚdž͖^&DsEĐŽŶĨŝƌŵĂƚŽƌLJ dƌĞĂƚŵĞŶƚ WŶĞƵŵŽŶŝƚŝƐ͗ǀĞƌLJƌĂƌĞŝŶ/^͕ƵƐƵĂůůLJďLJƐƚĂŶĚĞƌŝŶ sĂůŐĂŶĐŝĐůŽǀŝƌŽƌŐĂŶĐŝĐůŽǀŝƌ >ĂŶĚŶŽƚĐĂƵƐĞŽĨƉƵůŵŽŶĂƌLJĚŝƐĞĂƐĞ ĞƉĞŶĚƐŽŶĐůŝŶŝĐĂůĞŶƚŝƚLJ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘ tŚĂƚŝƐŽŶLJŽƵƌĚŝĨĨĞƌĞŶƚŝĂůĚŝĂŐŶŽƐŝƐ͍ dž͗tŽƌƐĞŶŝŶŐŽĨK/ĂĨƚĞƌƐƚĂƌƚŝŶŐZd /ŵŵƵŶĞƌĞĐŽŶƐƚŝƚƵƚŝŽŶŝŶĨůĂŵŵĂƚŽƌLJƐLJŶĚƌŽŵĞ;/Z/^Ϳ ϭ͘ DĞĚŝĐĂƚŝŽŶŶŽŶĂĚŚĞƌĞŶĐĞ ĚǀĞƌƐĞŵĞĚĞĨĨĞĐƚ dƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ Ϯ͘ EĞǁK/ EŽŶĂĚŚĞƌĞŶĐĞ ZĞƐŝƐƚĂŶĐĞΎ ϯ͘ /Z/^ WŽŽƌĂďƐŽƌƉƚŝŽŶŽĨŵĞĚŝĐĂƚŝŽŶƐ EĞǁK/ ϰ͘ dƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ DĂůŝŐŶĂŶĐLJ ƵƚŽŝŵŵƵŶĞĐŽŶĚŝƚŝŽŶ ϱ͘ ůůŽĨƚŚĞĂďŽǀĞ Ύ/ŶĚD͕ƐƵƐĐĞƉƚŝďŝůŝƚLJƚĞƐƚŝŶŐĨŽƌĐůĂƌŝƚŚƌŽŵLJĐŝŶ;ďƵƚŶŽŽƚŚĞƌĚƌƵŐƐͿĐŽƌƌĞůĂƚĞĚǁŝƚŚĐůŝŶŝĐĂůƌĞƐƉŽŶƐĞ _>IRRWHUWH[WKHUH@ tŚĂƚŝƐ/ŵŵƵŶĞZĞĐŽŶƐƚŝƚƵƚŝŽŶ/ŶĨůĂŵŵĂƚŽƌLJ ^LJŶĚƌŽŵĞ;/Z/^Ϳ͍ WĂƌĂĚŽdžŝĐĂůǀĞƌƐƵƐƵŶŵĂƐŬŝŶŐ/Z/^ 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ǁŝƚŚŽƵƚŚĞĂĚĂĐŚĞŽƌD^ ϭ͘WĞƌĨŽƌŵ>WƚŽĞǀĂůƵĂƚĞĨŽƌŵĞŶŝŶŐŝƚŝƐ KƌĚĞƌƐĞƌƵŵƌŐ ŝĨϰфϭϬϬĂŶĚĂŶLJŽĨƚŚĞĨŽůůŽǁŝŶŐ͗ Ϯ͘/ŶŝƚŝĂƚĞĨůƵĐŽŶĂnjŽůĞĨŽƌĐƌLJƉƚŽĐŽĐĐĂůƉŶĞƵŵŽŶŝĂ &ĞǀĞƌ͕ŚĞĂĚĂĐŚĞ͕D^͕ƉŶĞƵŵŽŶŝĂ WĞƌĨŽƌŵ>W ŝĨŶĞǁůLJƉŽƐŝƚŝǀĞƐĞƌƵŵƌŐ ;ĞǀĞŶŝĨĂƐLJŵƉƚŽŵĂƚŝĐͿ tĂƌĚϴϲDĂŶĂŐĞŵĞŶƚZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ͘,/s/Ŷ^ŝƚĞ͘ _>IRRWHUWH[WKHUH@ ĂƐĞϯĐŽŶƚŝŶƵĞĚ ƌLJƉƚŽĐŽĐĐĂůŵĞŶŝŶŐŝƚŝƐ ϰсϯϵ DŽƐƚĐĂƐĞƐŽĐĐƵƌǁŚĞŶϰфϭϬϬ >W͗KWϮϴĐŵ͕tϮ ;EϬ͕>ϵϯ͕DϳͿ͕ZϮ͕'ůƵ ϲϬ͕WƌŽƚ ϰϮ ^&ƌŐ ϭ͗ϭϮϴ ůŝŶŝĐĂů͗ ^&ĐdžŶĞŽĨŽƌŵĂŶƐ WƌĞƐĞŶƚƐĂƐƐƵďĂĐƵƚĞŵĞŶŝŶŐŝƚŝƐŽƌŵĞŶŝŶŐŽĞŶĐĞƉŚĂůŝƚŝƐ ĂŶĂůƐŽƐĞĞĞŶĐĞƉŚĂůŽƉĂƚŚŝĐƐŝŐŶƐͬƐdžĚƵĞƚŽĞůĞǀĂƚĞĚ/W /ŶĚƵĐĞĚƐƉƵƚƵŵн> ŝĂŐŶŽƐŝƐ͗ ŶĞŽĨŽƌŵĂŶƐ ^ĞƌƵŵĂŶĚ^&ƌŐĂƌĞĂůŵŽƐƚĂůǁĂLJƐƉŽƐŝƚŝǀĞ ^ŬŝŶďdž Đdž ^&ƐƚƵĚŝĞƐ͗ůLJŵƉŚŽĐLJƚŝĐƉůĞŽĐLJƚŽƐŝƐŽƌŶŽĐĞůůƐ͕ŵŝůĚůLJĞůĞǀĂƚĞĚƉƌŽƚĞŝŶ͕ŐůƵĐŽƐĞ ŶĞŽĨŽƌŵĂŶƐ ŶŽƌŵĂůƚŽůŽǁ͕ĞůĞǀĂƚĞĚKW >Žǁ^&tƉŽƌƚĞŶĚƐĂƉŽŽƌĞƌƉƌŽŐŶŽƐŝƐ ůŽŽĚĐdž ^&ĐƵůƚƵƌĞŝƐŐŽůĚͲƐƚĂŶĚĂƌĚ ŶĞŽĨŽƌŵĂŶƐ ƌŐ ƵƐĞĚĨŽƌĚŝĂŐŶŽƐŝƐ͕EKd ĞǀĂůƵĂƚŝŶŐƌĞƐƉŽŶƐĞƚŽƚŚĞƌĂƉLJʹ ŶĞĞĚĐƵůƚƵƌĞ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ ƌLJƉƚŽĐŽĐĐĂůŵĞŶŝŶŐŝƚŝƐ͗dƌĞĂƚŵĞŶƚ D͗DĂŝŶƐƚĂLJŽĨŵĂŶĂŐĞŵĞŶƚŝƐ ĐŽŶƚƌŽůŽĨĞůĞǀĂƚĞĚŝŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞ /ŶĚƵĐƚŝŽŶ;ĂƚůĞĂƐƚ ϭϰĚĂLJƐͿ͗ DŽŶŝƚŽƌĨŽƌ ůĞǀĂƚĞĚ/W >ŝƉŽƐŽŵĂů ĂŵƉŚŽƚĞƌŝĐŝŶ;ŵŝƐŽŵĞͿϯͲϰŵŐͬŬŐͬĚƉůƵƐ ĞůĞĐƚƌŽůLJƚĞĂďŶŽƌŵĂůŝƚŝĞƐ ;ŚLJƉŽŬĂůĞŵŝĂͿ ĐĂŶĐĂƵƐĞĐůŝŶŝĐĂůĚĞƚĞƌŝŽƌĂƚŝŽŶĞǀĞŶǁŝƚŚŵŝĐƌŽďŝŽůŽŐŝĐƌĞƐƉŽŶƐĞ &ůƵĐLJƚŽƐŝŶĞ;ϱͲ&ͿϭϬϬŵŐͬŬŐͬĚŝŶϰĚŝǀŝĚĞĚĚŽƐĞƐ ĐƌĞĂƚŝŶŝŶĞ ůĞĂĚŝŶŐĐĂƵƐĞŽĨĚĞĂƚŚĨƌŽŵDŝŶƚŚĞĨŝƌƐƚϮǁŬƐĂĨƚĞƌĚŝĂŐŶŽƐŝƐ ŽƐĞĂĚũƵƐƚŝŶƌĞŶĂůŝŵƉĂŝƌŵĞŶƚ ĐLJƚŽƉĞŶŝĂƐ 'ŝǀĞ/sĨůƵŝĚƐ;ŶŽƌŵĂůƐĂůŝŶĞͿ DĂŶĂŐĞŵĞŶƚ͗ /ĨƉĂƚŝĞŶƚŝŵƉƌŽǀŝŶŐнƌĞƉĞĂƚ^&ĐdžŶĞŐĂƚŝǀĞ DĞĂƐƵƌĞKWĂƚĚŝĂŐŶŽƐŝƐ /ĨKWŝƐĞůĞǀĂƚĞĚхϮϬĐŵ,ϮKĂŶĚƉƚŚĂƐƐdž͗ ŽŶƐŽůŝĚĂƚŝŽŶ;ϴǁĞĞŬƐͿ͗ >WĞǀĞƌLJϭϮͲϮϰŚŽƵƌƐƚŽƌĞŵŽǀĞǀŽůƵŵĞ;ΕϮϬͲϯϬĐĐͿƚŽďƌŝŶŐƚŚĞKWĚŽǁŶƚŽϮϬĐŵ &ůƵĐŽŶĂnjŽůĞϰϬϬŵŐ;ϲŵŐͬŬŐͿWKĚĂŝůLJ ,ϮKŽƌďLJϱϬй ŝŵĨŽƌĂƚůĞĂƐƚϮĚĂLJƐŽĨƐƚĂďůĞƉƌĞƐƐƵƌĞƐ ŽŶƐŝĚĞƌůƵŵďĂƌĚƌĂŝŶŝĨƐdž ƉĞƌƐŝƐƚ;ƌĞĨƌĂĐƚŽƌLJŚĞĂĚĂĐŚĞ͕Eͬs͕ĐŽŶĨƵƐŝŽŶ͕ ŚƌŽŶŝĐŵĂŝŶƚĞŶĂŶĐĞ;ĂƚůĞĂƐƚϭLJĞĂƌͿ͗ ĐůŽŶƵƐ͕ƉĂƉŝůůĞĚĞŵĂͿĚĞƐƉŝƚĞĚĂŝůLJ>WƐ &ůƵĐŽŶĂnjŽůĞϮϬϬŵŐWKĚĂŝůLJĨŽƌĂƚůĞĂƐƚϭLJĞĂƌ sĞŶƚƌŝĐƵůŽƉĞƌŝƚŽŶĞĂů;sWͿƐŚƵŶƚƐŚŽƵůĚŽŶůLJďĞƉůĂĐĞĚŝŶĞdžĐĞĞĚŝŶŐůLJƌĂƌĞ EϰхϭϬϬĂŶĚs>ƐƵƉƉƌĞƐƐĞĚdžϯŵŽŶƚŚƐŽŶZd ĐŝƌĐƵŵƐƚĂŶĐĞƐ;ĐĂŶŶŽƚĐŽŶƚƌŽů/WĂĨƚĞƌϮͲϰǁŬƐ ŽĨŵĂdžŝŵĂůƚŚĞƌĂƉLJͿ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘/^'ƵŝĚĞůŝŶĞƐ͕/ϮϬϭϬ͘ ,,^K/'ƵŝĚĞůŝŶĞƐϮϬϭϴ͘tĂƌĚϴϲDĂŶĂŐĞŵĞŶƚZĞĐŽŵŵĞŶĚĂƚŝŽŶƐ͕,/s/ŶƐŝƚĞ͘ _>IRRWHUWH[WKHUH@ tŚĞŶƐŚŽƵůĚLJŽƵƐƚĂƌƚZd͍ ^ƚĂƌƚŝŶŐZdĚƵƌŝŶŐĂŶĂĐƵƚĞK/ ϭ͘ EŽǁ ĚǀĂŶƚĂŐĞƐ ŝƐĂĚǀĂŶƚĂŐĞƐ ^ŽŵĞƚŝŵĞƐZdŝƐƚŚĞďĞƐƚ ZŝƐŬŽĨ/Z/^ ƚƌĞĂƚŵĞŶƚĨŽƌƚŚĞK/ Ϯ͘ ĨƚĞƌϮǁĞĞŬƐ ĞƐƉĞĐŝĂůůLJŝĨŽĐĐƵƌƐŝŶE^ŽƌĞLJĞ WD>͕ĐƌLJƉƚŽƐƉŽƌŝĚŝŽƐŝƐ͕ ŵŝĐƌŽƐƉŽƌŝĚŝŽƐŝƐ ϯ͘ ĨƚĞƌϲǁĞĞŬƐ WƌĞǀĞŶƚŝŽŶŽĨĂƐĞĐŽŶĚK/ ZĞƐƚŽƌĞƉĂƚŚŽŐĞŶͲƐƉĞĐŝĨŝĐ ŝŵŵƵŶŝƚLJ;ŵŽƌĞƌĂƉŝĚĐůĞĂƌĂŶĐĞŽĨ ϰ͘ ĨƚĞƌϭϬǁĞĞŬƐ K/Ϳ ^ůŽǁ,/sƉƌŽŐƌĞƐƐŝŽŶ tŚĞŶƚŽƐƚĂƌƚZdŝŶĐƌLJƉƚŽĐŽĐĐĂůŵĞŶŝŶŐŝƚŝƐ͍ KddƌŝĂů͗ ϭϳϳƉƚƐŝŶhŐĂŶĚĂн^ŽƵƚŚĨƌŝĐĂ DZdž͗ ŵƉŚŽƚĞƌŝĐŝŶн&ůƵĐŽŶĂnjŽůĞ ϴϬϬŵŐĚĂŝůLJdžϮǁĞĞŬƐ͕ ϮϴϮƉĂƚŝĞŶƚƐǁŝƚŚĂĐƵƚĞK/ŽƌƐĞƌŝŽƵƐďĂĐƚĞƌŝĂůŝŶĨĞĐƚŝŽŶ ƚŚĞŶ&ůƵĐ ϴϬϬƵŶƚŝů^&ƐƚĞƌŝůĞ ϲϯйWW͕ϭϮйĐƌLJƉƚŽĐŽĐĐƵƐ͕ĞdžĐůƵĚĞĚd͖ŵĞĚŝĂŶϰϮϵ ƚŚĞŶ&ůƵĐ ϰϬϬdžϴǁŬƐ ZĂŶĚŽŵŝnjĞĚƚŽ͗ ^ƚŽƉƉĞĚĞĂƌůLJͲ ĞdžĐĞƐƐŵŽƌƚĂůŝƚLJ ͞ ĂƌůLJZd͟сǁŝƚŚŝŶϮǁŬƐŽĨƐƚĂƌƚŝŶŐƚŚĞƌĂƉLJĨŽƌK/;ŵĞĚŝĂŶϭϮĚĂLJƐ͕Ϳ ĂƌůŝĞƌZd;ŶсϴϴͿ ĞĨĞƌƌĞĚZd;ŶсϴϵͿ ͞ĞĨĞƌƌĞĚZd͟сĂĨƚĞƌK/ƚƌĞĂƚŵĞŶƚĐŽŵƉůĞƚĞ;ĂƚϲͲϭϮǁŬƐͿ;ŵĞĚŝĂŶϰϱĚĂLJƐͿ dŝŵŝŶŐŽĨZdƐƚĂƌƚ͕ŵĞĚŝĂŶ;/YZͿ ϵĚĂLJƐ;ϴͲϵͿ ϯϲĚĂLJƐ;ϯϰͲϯϴͿ 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dƌĂŶƐŝĞŶƚĞůĂƐƚŽŐƌĂƉŚLJ ;&ŝďƌŽƐĐĂŶͿ ůďƵŵŝŶ dž ƌ dž ,s/Ő' dž dž;,ĐďнсĞǀŝĚĞŶĐĞŽĨ ƉƌŝŽƌŝŶĨĞĐƚŝŽŶ͕ ,s͗ƐŐ͕ Ɛď͕Đď ƌŝƐŬĨŽƌƌĞĂĐƚŝǀĂƚŝŽŶͿ ,/sZE dž WZ/с^dƚŽWůĂƚĞůĞƚZĂƚŝŽ/ŶĚĞdž &/Ͳϰ;ĨŝďƌŽƐŝƐͲϰͿ ŚƚƚƉ͗ͬͬǁǁǁ͘ŚĞƉĂƚŝƚŝƐĐ͘Ƶǁ͘ĞĚƵͬƉĂŐĞͬĐůŝŶŝĐĂůͲĐĂůĐƵůĂƚŽƌƐͬĨŝďͲϰ ŚƚƚƉ͗ͬͬǁǁǁ͘ŚĞƉĂƚŝƚŝƐĐ͘Ƶǁ͘ĞĚƵͬƉĂŐĞͬĐůŝŶŝĐĂůͲĐĂůĐƵůĂƚŽƌƐͬĂƉƌŝ фϭ͘ϰϱÆ ůŽǁůŝŬĞůŝŚŽŽĚŽĨĂĚǀĂŶĐĞĚĨŝďƌŽƐŝƐͬĐŝƌƌŚŽƐŝƐ хϬ͘ϳÆ ƉŽƐƐŝďůĞ͞ƐŝŐŶŝĨŝĐĂŶƚĨŝďƌŽƐŝƐ͟;&ϮнĨŝďƌŽƐŝƐͿ ^ĞŶƐ͘ϳϳй^ƉĞĐ͘ϳϮй EWsϵϬй хϭ͘ϬÆ ƉŽƐƐŝďůĞĐŝƌƌŚŽƐŝƐ;&ϰͿ ^ĞŶƐ͘ϳϲй^ƉĞĐ͘ϳϮй хϯ͘ϮϱÆ ĂĚǀĂŶĐĞĚĨŝďƌŽƐŝƐͬĐŝƌƌŚŽƐŝƐ ^ƉĞĐϵϳй͕WWsϲϱй хϮ͘ϬÆ ƉƌŽďĂďůĞĐŝƌƌŚŽƐŝƐ ^ĞŶƐ ϰϲй͕^ƉĞĐϵϭй >ŝŶ,ĞƚĂů͘,ĞƉĂƚŽůŽŐLJ͘ϮϬϭϭ͘ ^ƚĞƌůŝŶŐZ<Ğƚ͘Ăů͘,ĞƉĂƚŽůŽŐLJϮϬϬϲ͘ ϯ ϭϭͬϯϬͬϮϬϭϴ &ŝďƌŽƐŝƐĞǀĂůƵĂƚŝŽŶ ĂƐĞϭ WŚLJƐŝĐĂů džĂŵ͗ƉĂůŵĂƌĞƌLJƚŚĞŵĂ͕ ϯϱDǁŝƚŚ,/s͕ĐŚƌŽŶŝĐ,s͕ƉƌŝŽƌŚdž /sh ƚĞůĂŶŐĞĐƚĂƐŝĂ͕ƐƉůĞŶŽŵĞŐĂůLJ͕ĞƚĐ ,sǀŝƌĂůůŽĂĚϱŵŝůůŝŽŶ/hͬŵ>͕ŐĞŶŽƚLJƉĞϭĂ ^dр ^d;hƉƉĞƌůŝŵŝƚŽĨŶŽƌŵĂůͿ EŽŶͲŝŶǀĂƐŝǀĞŵĂƌŬĞƌƐ͗ WZ/с džϭϬϬ ,sŝŵŵƵŶĞ͕,sŝŵŵƵŶĞ;Ɛď ĂŶĚĐŽƌĞďƉŽƐ͕ƐŐ ŶĞŐͿ WůĂƚĞůĞƚĐŽƵŶƚ;ϭϬϿͬ>Ϳ ^d͕>d͕/EZ͕ĂůďƵŵŝŶ͕ƉůĂƚĞůĞƚƐ ,/sZEфϰϬ͕E &/Ͳϰ͕WZ/͕&ŝďƌŽ^ƵƌĞͬ&ŝďƌŽdĞƐƚ ^dϰϱ͕>dϳϲ dƌĂŶƐŝĞŶƚĞůĂƐƚŽŐƌĂƉŚLJ ;&ŝďƌŽƐĐĂŶͿ ,Őďϭϰ͕WůĂƚĞůĞƚƐϭϵϵ ͻ /ŵĂŐŝŶŐ͗hůƚƌĂƐŽƵŶĚĨŽƌ,͕ WZ/͗Ϭ͘ϲϰ͕&/Ͳϰ͗Ϭ͘ϵϭÆ ůŝŬĞůLJŶŽŶͲĐŝƌƌŚŽƚŝĐ ƐƉůĞŶŽŵĞŐĂůLJ͕ŶŽĚƵůĂƌŝƚLJ͕ĞƚĐ ďĚŽŵŝŶĂůƵůƚƌĂƐŽƵŶĚ͗ĐŽĂƌƐĞ͕ŚĞƚĞƌŽŐĞŶĞŽƵƐĂŶĚŚLJƉĞƌĞĐŚŽŝĐ ͻ ŝŽƉƐLJ͗ƌĂƌĞůLJŶĞĞĚĞĚ ůŝǀĞƌ͕ŶŽĞǀŝĚĞŶĐĞŽĨĐŝƌƌŚŽƐŝƐŽƌƉŽƌƚĂůŚLJƉĞƌƚĞŶƐŝŽŶ 'ĞŶŽƚLJƉĞϭ͕ŝŶĐůƵĚŝŶŐŶŽŶͲ ƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞĂŶĚĐŽŵƉĐŝƌƌŚŽƐŝƐ ,ĞůƉŵĞĐŚŽŽƐĞ͊ ZĞŐŝŵĞŶ ŽƐĞ ƵƌĂƚŝŽŶ Ă 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ ϯƚĂďƐĚĂŝůLJ ϴ ͲϭϮǁŬƐ tŝƚŚƐĞǀĞƌĂůĚŝĨĨĞƌĞŶƚŽƉƚŝŽŶƐ͕ŚŽǁĚŽ/ƉŝĐŬĂƌĞŐŝŵĞŶ͍͍͍ ;DĂǀLJƌĞƚͿ '> ͬW/ ϭͿ&ŽĐƵƐŽŶĐŽŵŽƌďŝĚĐŽŶĚŝƚŝŽŶƐʹ ƐŽŵĞƐĂĨĞƚLJĐŽŶĐĞƌŶƐ ůďĂƐǀŝƌͬ'ƌĂnjŽƉƌĞǀŝƌ ϭƚĂďĚĂŝůLJ ϭϮͲϭϲď ǁŬƐ ϮͿ&ŽĐƵƐŽŶŽƚŚĞƌŵĞĚŝĐĂƚŝŽŶƐʹ ůŽŽŬĨŽƌŝŶƚĞƌĂĐƚŝŽŶƐ ;ĞƉĂƚŝĞƌͿ Zͬ'Z;нͬͲ ZsͿď ϯͿ&ŽĐƵƐŽŶŝŶƐƵƌĂŶĐĞƌĞƋƵŝƌĞŵĞŶƚƐʹ ǁŚĂƚŝƐĐŽǀĞƌĞĚ >ĞĚŝƉĂƐǀŝƌͬ^ŽĨŽƐďƵǀŝƌ ϭƚĂďĚĂŝůLJ ϴĚͲϭϮ ǁŬƐ ϰͿ&ŽĐƵƐŽŶĚƵƌĂƚŝŽŶĂŶĚƉŝůůďƵƌĚĞŶʹ ůĞƐƐŝƐŵŽƌĞ ;,ĂƌǀŽŶŝͿ >sͬ^K&;нͬͲ ZsͿĐ sĞůƉĂƚĂƐǀŝƌͬ^ŽĨŽƐďƵǀŝƌ ϭƚĂďĚĂŝůLJ ϭϮǁŬƐ ; ƉĐůƵƐĂͿ s >ͬ^K& ĂͿ^>ͬ/^ŐƵŝĚĞůŝŶĞƐƌĞĐϭϮǁŬƐ ŝĨĐŽŵƉĐŝƌƌŚŽƐŝƐ͖ϴǁŬƐ ůŝŬĞůLJK<ƉĞƌ džƉĞĚŝƚŝŽŶϴ ďͿ'dϭĂŶĞĞĚƐE^ϱZ^ŐĞŶŽƚLJƉĞÆ ϭϲǁŬƐ нZsŝĨƌĞƐŝƐƚĂŶĐĞƉƌĞƐĞŶƚ ĐͿZsĂĚĚĞĚŝĨĐŽŵƉĐŝƌƌŚŽƐŝƐEƉƌŝŽƌWĞŐͲ/ͬZsĨĂŝůƵƌĞ ĚͿϴǁĞĞŬƐŽŶůLJŝĨŶŽŶͲďůĂĐŬ͕ŶŽ,/s͕,sZEфϲŵŝůůŝŽŶ/hͬŵ> ŚƚƚƉ͗ͬͬǁǁǁ͘ŚĐǀŐƵŝĚĞůŝŶĞƐ͘ŽƌŐͬ ϰ ϭϭͬϯϬͬϮϬϭϴ Z^YƵĞƐƚŝŽŶ /ŵƉŽƌƚĂŶƚŽŵŽƌďŝĚŝƚŝĞƐ ZĞŶĂůĚŝƐĞĂƐĞ tŚŝĐŚĐŽŵŽƌďŝĚĐŽŶĚŝƚŝŽŶ͕ŝĨƉƌĞƐĞŶƚ͕ƐŚŽƵůĚ/ďĞŵŽƐƚ ǀŽŝĚ^K&ĨŽƌƌ> фϯϬ ĐŽŶĐĞƌŶĞĚĂďŽƵƚ͍ >ͬ'Z;ĞƉĂƚŝĞƌͿŽƌ'> ͬW/;DĂǀLJƌĞƚͿĂƌĞŽŬĨŽƌƌů фϯϬ ͿŚƌŽŶŝĐŬŝĚŶĞLJĚŝƐĞĂƐĞ Θ ^Z Ϳ' Z ' Zͬ'ĂƐƚƌŝƚŝƐ WW/ŶŽƚĐŽŵƉĂƚŝďůĞǁŝƚŚ>sŽƌs >;ŝŶ,ĂƌǀŽŶŝ͕ ƉĐůƵƐĂͿ ͿŶĞŵŝĂ ͿŚƌŽŶŝĐ,ĞƉĂƚŝƚŝƐ ŶĞŵŝĂ /ĨƌŝďĂǀŝƌŝŶͲĐŽŶƚĂŝŶŝŶŐƌĞŐŝŵĞŶŝƐŝŶĚŝĐĂƚĞĚ ͿůůŽĨƚŚĞĂďŽǀĞ ,s ZŝƐŬĨŽƌƌĞͲĂĐƚŝǀĂƚŝŽŶŝĨ,sƐƵƌĨĂĐĞŐŽƌĐŽƌĞďн͖ ƐŐнƐŚŽƵůĚďĞŽŶ,sͲĂĐƚŝǀĞƚŚĞƌĂƉLJ;ϯdͬ&dͬd&ͬd&Ϳ ͲZdŝŶƚĞƌĂĐƚŝŽŶƐ;ƚƌĞĂƚŵĞŶƚͲŶĂŢǀĞƌĞĐŽŵŵĞŶĚĞĚƌĞŐŝŵĞŶƐͿ */(3,% 62)9(/ /'962) (/%*5= DŽƐƚĐŽŵŵŽŶĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐ 0DY\UHW (SFOXVD +DUYRQL =HSDWLHU dsͬƌ E јs >͕d ј>s͕ d ј >͕'Z͕d ůďĂƐǀŝƌͬ'ƌĂnjŽƉƌĞǀŝƌ;ĞƉĂƚŝĞƌͿΘ'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ Zsͬƌ EΎ ўs >͕ Zs ј>s͕ ўZs ј >͕'Z͕ўZs ;DĂǀLJƌĞƚͿ >Wsͬƌ EΎ ўs >͕ >Ws E ј >͕'Z͕ў>Ws DĂŶLJŝŶƚĞƌĂĐƚŝŽŶƐǁŝƚŚ,/sĂŶƚŝͲƌĞƚƌŽǀŝƌĂůƐ &s E E љ>s͕ &s E ^ŽŵĞĐŽŶƚƌĂŝŶĚŝĐĂƚĞĚ͕ĞƐƉ ƌŝƚŽŶĂǀŝƌͲƐƚĞĚƉƌŽƚĞĂƐĞŝŶŚŝďŝƚŽƌƐ ZWs јZWs͕ў'ͬW ўs >͕ ZWs ў>s͕ZWs ў >͕'Z͕ZWs ds E E E E >ĞĚŝƉĂƐǀŝƌĂŶĚ sĞůƉĂƚĂƐǀŝƌ ;ƉĂƌƚŽĨ,ĂƌǀŽŶŝĂŶĚ ƉĐůƵƐĂͿ Z> јZ>͕ў'ͬW ўs >͕ Z> ў>s͕Z> ў >͕'Z͕јZ> ZĞĚƵĐĞĚĚƌƵŐůĞǀĞůƐǁŝƚŚĂĐŝĚďůŽĐŬŝŶŐŵĞĚƐ ;ĂŶƚĂĐŝĚƐ͕,ϮďůŽĐŬĞƌƐ͕WW/ƐͿ >sͬĐ ј'> ͕ W/͕K јs >͕ K ј>s͕ K ј >͕'Z͕K d' љ'> ͕W/јd' ўs >͕ d' ў>s͕d' ў >͕'Z͕јd' ^ŽĨŽƐďƵǀŝƌ ǁŝƚŚĂŵŝŽĚĂƌŽŶĞ Ds E E E E ůĂĐŬŽdž͊ d& E ўs >͕ јd&s ў>s͕јd&s ў >͕'Z͕јd&s d& ў'> ͕W/͕d&s ўs >͕ јd&s ў>s͕јd&s E Eʹ ŶŽĚĂƚĂ͖Z сĂǀŽŝĚ͕'Z EсƐĂĨĞ͕z >>KtсĚŽƐĞĐŚĂŶŐĞͬŵŽŶŝƚŽƌ KZE' ͬΎW<ĚĂƚĂƐƵƉƉŽƌƚĐŽͲĂĚŵŝŶŝƐƚƌĂƚŝŽŶ ŚƚƚƉƐ͗ͬͬǁǁǁ͘ŚĐǀŐƵŝĚĞůŝŶĞƐ͘ŽƌŐͬ ϱ ϭϭͬϯϬͬϮϬϭϴ ZĞĂĚLJ͙ƐĞƚ͙ ŶĚƵƌĂŶĐĞƚƌŝĂůƐ zŽƵƌƉĂƚŝĞŶƚŝƐŵŽƚŝǀĂƚĞĚƚŽƐƚĂƌƚ,sƚŚĞƌĂƉLJ d&ͬ&dͬ >sͬĐ;'ĞŶǀŽLJĂͿĨŽƌZd ŶĚƵƌĂŶĐĞϭ͗'dϭ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐ͕ŝŶĐůƵĚĞĚ,/sĂŶĚ ŽŶƚƌĂŝŶĚŝĐĂƚĞĚǁŝƚŚĞůďĂƐǀŝƌͬŐƌĂnjŽƉƌĞǀŝƌ;ĞƉĂƚŝĞƌͿ ƚƌĞĂƚŵĞŶƚĞdžƉĞƌŝĞŶĐĞĚ;ŝŶĐů ^K&Ϳ KŬƚŽŵŽŶŝƚŽƌǁŝƚŚŽƚŚĞƌƐ 'ͬWdžϴǁŬƐ ǀƐϭϮǁŬƐ DĞƚŚĂĚŽŶĞŵĂŝŶƚĞŶĂŶĐĞƚŚĞƌĂƉLJ KŬǁŝƚŚĂůůĐƵƌƌĞŶƚĨŝƌƐƚͲůŝŶĞ,sƌĞŐŝŵĞŶƐ ŶĚƵƌĂŶĐĞϮ͕ϰ͗'dϮŽƌ'dϰͲϲ͕ƌĞƐƉĞĐƚŝǀĞůLJ͕ƚƌĞĂƚŵĞŶƚ ůƐŽƚĂŬŝŶŐWW/ĨŽƌŚŝƐƚŽƌLJŽĨƉĞƉƚŝĐƵůĐĞƌƐůĂƐƚLJĞĂƌ ŶĂŢǀĞĂŶĚĞdžƉĞƌŝĞŶĐĞĚ;ŝŶĐů ^K&Ϳ ǀŽŝĚWW/ǁŝƚŚ>sŽƌs >ŝĨƉŽƐƐŝďůĞ;ŝŶ,ĂƌǀŽŶŝ͕ ƉĐůƵƐĂͿ 'ͬWdžϭϮǁŬƐ͕ƉůĂĐĞďŽͲĐŽŶƚƌŽůůĞĚ ŶĚƵƌĂŶĐĞϯ͗'dϯ͕ŶŽŶͲĐŝƌƌŚŽƚŝĐ͕ƚƌĞĂƚŵĞŶƚŶĂŢǀĞ /ŶƐƵƌĂŶĐĞĂƉƉƌŽǀĞƐŐůĞĐĂƉƌĞǀŝƌͬƉŝďƌĞŶƚĂƐǀŝƌ ;DĂǀLJƌĞƚͿ͊͊͊ 'ͬWdžϭϮǁŬƐ ŽƌϴǁŬƐ ǀƐ^K&ͬsdžϭϮǁŬƐ ĞƵnjĞŵ͕ĞƚĂů͘E ŶŐů :DĞĚϮϬϭϴ͖ϯϳϴ͗ϯϱϰͲϯϲϵ ŶĚƵƌĂŶĐĞͲϭ džƉĞĚŝƚŝŽŶƚƌŝĂůƐ ZĞƐƵůƚƐ͗ ϴǁĞĞŬƐĂƐ ůůƌĞĐĞŝǀĞĚϭϮǁĞĞŬƐŽĨ'ͬW͗ ŐŽŽĚĂƐϭϮǁĞĞŬƐ͕ ŝŶĐůƵĚŝŶŐĨŽƌ,/s džƉĞĚŝƚŝŽŶϭ͗'dϭ͕Ϯ͕ϰͲϲ͕ĐŽŵƉĞŶƐĂƚĞĚĐŝƌƌŚŽƐŝƐ͕ŝŶĐůƵĚĞĚ ŝŶĨĞĐƚĞĚƉĂƚŝĞŶƚƐ͕ ƚƌĞĂƚŵĞŶƚĞdžƉĞƌŝĞŶĐĞĚ ĂŶĚŝŶĐůƵĚŝŶŐƉƌŝŽƌ džƉĞĚŝƚŝŽŶϮ͗'dϭ͕Ϯ͕ϰͲϲ͕,/sĐŽͲŝŶĨĞĐƚĞĚнĐŽŵƉĞŶƐĂƚĞĚ ƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞƐ ĐŝƌƌŚŽƐŝƐ͕ŝŶĐůƵĚĞĚƚƌĞĂƚŵĞŶƚĞdžƉĞƌŝĞŶĐĞĚ džƉĞĚŝƚŝŽŶϰ͗'dϭͲϲ͕ǁŝƚŚ<^ƚĂŐĞϰͲϱŝŶĐůƵĚŝŶŐ, dŚĞƐĞĂƌĞŶŽŶͲ ĐŝƌƌŚŽƚŝĐƉĂƚŝĞŶƚƐ >ĂŶĐĞƚ /ŶĨĞĐƚ ŝƐ͘ ϮϬϭϳKĐƚ͖ϭϳ;ϭϬͿ͗ϭϬϲϮͲϭϬϲϴ͘ ůŝŶ /ŶĨĞĐƚŝƐ͘ ϮϬϭϴ^ĞƉϭϰ͖ϲϳ;ϳͿ͗ϭϬϭϬͲϭϬϭϳ͘ ĞƵnjĞŵ͕ĞƚĂů͘E ŶŐů :DĞĚϮϬϭϴ͖ϯϳϴ͗ϯϱϰͲϯϲϵ E ŶŐů :DĞĚϮϬϭϳ͖ϯϳϳ͗ϭϰϰϴͲϭϰϱϱ͘ ϲ ϭϭͬϯϬͬϮϬϭϴ ^ůŝĚĞĨƌŽŵŶŶŝĞ>ƵĞƚŬĞŵĞLJĞƌ džƉĞĚŝƚŝŽŶƚƌŝĂůƐ ,/sĞdžĐůƵĚĞĚ 'dϯĞŶƌŽůůĞĚďƵƚ ŶŽƌĞƐƵůƚƐLJĞƚ ZĞƐƵůƚƐ͗ŽŵƉĞŶƐĂƚĞĚ ĐŝƌƌŚŽƚŝĐƐ ĚŝĚŐƌĞĂƚǁŝƚŚ ϭϮǁĞĞŬƐŽĨ'ͬW͕ ŝŶĐůƵĚŝŶŐ,/sĐŽŝŶĨĞĐƚĞĚ ĂŶĚƉĂƚŝĞŶƚƐǁŝƚŚƌĞŶĂů ĨĂŝůƵƌĞ KǀĞƌĂůů^sZƌĂƚĞƐϵϴͲ ϭϬϬйĂĐƌŽƐƐƚŚĞďŽĂƌĚ ŝĚŶŽƚŝŶĐůƵĚĞ'dϯ d< ,KD ͗ŶƚŝĐŝƉĂƚĞϴǁĞĞŬƐŽĨ 'ͬWĨŽƌĐŝƌƌŚŽƚŝĐƐ ǁŝůůďĞĂĚŽƉƚĞĚŝŶ ŐƵŝĚĞůŝŶĞƐ >ĂŶĐĞƚ/ŶĨĞĐƚŝƐ͘ ϮϬϭϳKĐƚ͖ϭϳ;ϭϬͿ͗ϭϬϲϮͲϭϬϲϴ͘ ƌŽǁŶ^>ϮϬϭϴη 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ 'ĞŶŽƚLJƉĞϭdĂŬĞͲ,ŽŵĞWŽŝŶƚƐ ;DĂǀLJƌĞƚͿ &ŽƵƌŽƉƚŝŽŶƐǁŝƚŚĞdžĐĞůůĞŶƚ^sZϭϮ WŽƐŝƚŝǀĞƐ͙ <ĞĞƉŝŶŵŝŶĚ͙ hůƚŝŵĂƚĞĐŚŽŝĐĞǁŝůůĚĞƉĞŶĚŽŶ/Ɛ͕ĐŽŵŽƌďŝĚŝƚŝĞƐ͕ŝŶƐƵƌĂŶĐĞ ƉƉƌŽǀĞĚĨŽƌ'dϭʹ ϲ ϯƚĂďƐƉĞƌĚŽƐĞ >sͬ^K&;,ĂƌǀŽŶŝͿĂŶĚs >ͬ^K&; ƉĐůƵƐĂͿĂƌĞƐƚŝůůŐŽŽĚ ĂŶďĞƵƐĞĚŝŶĂĚǀĂŶĐĞĚƌĞŶĂů ĂŶŶŽƚƵƐĞǁŝƚŚďŽŽƐƚĞĚds͕ s >ͬ^K&ŝƐƉĂŶͲŐĞŶŽƚLJƉŝĐ ĨĂŝůƵƌĞ͕ŝŶĐů , dZŽƌ &s ǀŽŝĚǁŝƚŚĂĚǀĂŶĐĞĚ<͕ĐĂƵƚŝŽŶǁŝƚŚWW/Ɛ DĂŶLJƉƚ ĐƵƌĞĚǁŝƚŚϴǁĞĞŬƐ ůĞǀĂƚĞĚ>&dǁŝƚŚĂƚĂnjĂŶĂǀŝƌͬƌ ;ŝŶĐů 'dϭĐŽŵƉĐŝƌƌŚŽƚŝĐƐͿ ĞĐƌĞĂƐĞĚƚŚĞƌĂƉĞƵƚŝĐĞĨĨĞĐƚŽĨ /ĨĐŽŶƐŝĚĞƌŝŶŐ >ͬ'Z;ĞƉĂƚŝĞƌͿĨŽƌ'ĞŶŽƚLJƉĞϭĂ͕ƐĞŶĚƚĞƐƚŝŶŐ 'ͬWǁŝƚŚĞĨĂǀŝƌĞŶnj ĨŽƌďĂƐĞůŝŶĞE^ϱZ^ EŽƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐŶĞĞĚĞĚ /ĨƉƌĞƐĞŶƚĞdžƚĞŶĚƚƌĞĂƚŵĞŶƚƚŽϭϲǁĞĞŬƐĂŶĚĂĚĚƌŝďĂǀŝƌŝŶ KŬǁŝƚŚŚŝƐƚŽƌLJŽĨƉƌŝŽƌ ƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞ͕ŝŶĐů ^K&Ͳ '> ͬW/;DĂǀLJƌĞƚͿŝƐĂŐŽŽĚŽƉƚŝŽŶĂŶĚƉĂŶͲŐĞŶŽƚLJƉŝĐ ďĂƐĞĚƚŚĞƌĂƉLJ ϴǁĞĞŬƐŽĨƚƌĞĂƚŵĞŶƚŝŶĐů ĨŽƌĐŽŵƉĐŝƌƌŚŽƚŝĐƐ tĂƚĐŚŽƵƚĨŽƌ/ǁŝƚŚds͕ĂŶLJƐƚĞĚW/͕ &s͕ ds ϳ ϭϭͬϯϬͬϮϬϭϴ ĂƐĞϮ Z^YƵĞƐƚŝŽŶ ϱϬ&ǁŝƚŚ,/sĂŶĚĐŚƌŽŶŝĐ,sŐĞŶŽƚLJƉĞ ϯ EŽĐŝƌƌŚŽƐŝƐ͕ŶŽƉƌŝŽƌ ƚƌĞĂƚŵĞŶƚ ŚŝƐƚŽƌLJ tŚĂƚƐŚŽƵůĚLJŽƵƚĞůůŚĞƌĂďŽƵƚ,sƚŚĞƌĂƉLJĨŽƌŐĞŶŽƚLJƉĞϯ͍ ƌ Ϭ͘ϴϬ;'&ZхϲϬͿ͕,Őďϭϰ͕ŶŽƌŵĂů>&dƐĂŶĚ/EZ ͿůůƌĞŐŝŵĞŶƐĨŽƌŐĞŶŽƚLJƉĞϯƌĞƋƵŝƌĞďĂƐĞůŝŶĞƌĞƐŝƐƚĂŶĐĞƚĞƐƚŝŶŐ ,sͬ,sŝŵŵƵŶĞ;ƐďƉŽƐ͕ĐŽƌĞďŶĞŐ͕ƐŐŶĞŐͿ ͿůůƌĞŐŝŵĞŶƐĨŽƌŐĞŶŽƚLJƉĞϯƌĞƋƵŝƌĞƌŝďĂǀŝƌŝŶ;ZsͿ ZsƐ͗d&ͬ&dнdsͬƌ ͿŝƌƌŚŽƐŝƐĂŶĚƉƌŝŽƌƚƌĞĂƚŵĞŶƚĐĂŶƐŝŐŶŝĨŝĐĂŶƚůLJŝŵƉĂĐƚ^sZ ͿůůŽĨƚŚĞĂďŽǀĞ ͲZdŝŶƚĞƌĂĐƚŝŽŶƐ;ƚƌĞĂƚŵĞŶƚͲŶĂŢǀĞƌĞĐŽŵŵĞŶĚĞĚƌĞŐŝŵĞŶƐͿ */(3,% 62)9(/ /'962) (/%*5= 'ĞŶŽƚLJƉĞϯ͕ŝŶĐůƵĚŝŶŐĐŽŵƉĐŝƌƌŚŽƐŝƐ 0DY\UHW (SFOXVD +DUYRQL =HSDWLHU dsͬƌ E јs >͕d ј>s͕ d ј >͕'Z͕d Zsͬƌ EΎ ўs >͕ Zs ј>s͕ ўZs ј >͕'Z͕ўZs ZĞŐŝŵĞŶ ŽƐĞ ƵƌĂƚŝŽŶ >Wsͬƌ EΎ ўs >͕ >Ws E ј >͕'Z͕ў>Ws Ă 'ůĞĐĂƉƌĞǀŝƌͬWŝďƌĞŶƚĂƐǀŝƌ ϯƚĂďƐĚĂŝůLJ ϴ ͲϭϮǁŬƐ &s E E љ>s͕ &s E ;DĂǀLJƌĞƚͿ '> ͬW/ ZWs јZWs͕ў'ͬW ўs >͕ ZWs ў>s͕ZWs ў >͕'Z͕ZWs sĞůƉĂƚĂƐǀŝƌͬ^ŽĨŽƐďƵǀŝƌ ϭƚĂďĚĂŝůLJ ϭϮǁŬƐ ds E E E E ; ƉĐůƵƐĂͿ s >ͬ^K&;нͬͲ ZsͿď Z> јZ>͕ў'ͬW ўs >͕ Z> ў>s͕Z> ў >͕'Z͕јZ> >sͬĐ ј'> ͕ W/͕K јs >͕ K ј>s͕ K ј >͕'Z͕K 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ǁĞĞŬƐŽĨƚŚĞƌĂƉLJ 'ĞŶŽƚLJƉĞ͕ĨŝďƌŽƐŝƐƐƚĂŐĞ͕ƚƌĞĂƚŵĞŶƚĞdžƉĞƌŝĞŶĐĞ͕ ĐŽŵŽƌďŝĚŝƚŝĞƐ͕ĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐĂŶĚŝŶƐƵƌĂŶĐĞĐŽǀĞƌĂŐĞǁŝůů ĂůůŝŶĨŽƌŵƚŚĞƌĂƉLJĐŚŽŝĐĞƐ ,/sŝƚƐĞůĨĚŽĞƐŶŽƚƐĞĞŵƚŽŝŵƉĂĐƚ^sZ͕ďƵƚZdŵƵƐƚďĞ ĐŽŶƐŝĚĞƌĞĚ ,ĂƌĚĞƐƚƚŽƚƌĞĂƚƉŽƉƵůĂƚŝŽŶƐƐƚŝůůŶĞĞĚůŽŶŐĞƌƚŚĞƌĂƉLJнͬͲ ƌŝďĂǀŝƌŝŶ DŽƐƚŶŽƚĂďůĞŝŶ'dϯǁŝƚŚŚŝƐƚŽƌLJŽĨƚƌĞĂƚŵĞŶƚĨĂŝůƵƌĞŽƌĐŝƌƌŚŽƐŝƐ ŽŶƚŝŶƵĞƚŽŵŽŶŝƚŽƌĐŝƌƌŚŽƚŝĐƐ ĨŽƌ,͕ĂŶĚĞĚƵĐĂƚĞн ƐĐƌĞĞŶƉĂƚŝĞŶƚƐĨŽƌƌĞͲŝŶĨĞĐƚŝŽŶ ,ŝůů^>ϮϬϭϰďƐƚƌĂĐƚϰϰ ĐŬŶŽǁůĞĚŐĞŵĞŶƚƐ 'ƵŝĚĞůŝŶĞƐ,ĞůƉ ŚƚƚƉ͗ͬͬǁǁǁ͘ŚĐǀŐƵŝĚĞůŝŶĞƐ͘ŽƌŐ ŶŶŝĞ>ƵĞƚŬĞŵĞLJĞƌ DĂŶĂŐĞŵĞŶƚŐƵŝĚĞůŝŶĞƐĨƌŽŵ/^ĂŶĚ^> ZĂĐŚĞůZƵƚŝƐŚĂƵƐĞƌ DĞŐEĞǁŵĂŶ ŚƚƚƉ͗ͬͬǁǁǁ͘ŚĞƉͲĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐ͘ŽƌŐ ŝĂŶĞ,Ăǀůŝƌ &ƌĞĞĚŽǁŶůŽĂĚĂďůĞĂƉƉ DŽŶŝĐĂ'ĂŶĚŚŝ WĂƌLJĂ ^ĂďĞƌŝ ǁǁǁ͘ŚĐǀĂĚǀŽĐĂƚĞ͘ŽƌŐ sĂůZŽďď 'ƌĞĂƚƉĂƚŝĞŶƚŝŶĨŽƌŵĂƚŝŽŶ ĂŶĞƌƌŶĞƌ >ŝůůŝĂŶƌŽǁŶ ϭϭ Disclosure HCVPharmacologyfor • Ihavenothingtodisclose. AllClinicians ParyaSaberi,PharmD,MAS AssistantProfessor,UCSFCenterforAIDSPreventionStudies MedicalManagementofHIV/AIDSandHepatitis December2018 Resources Resources • AASLD/IDSA: • UniversityofLiverpool: – HEPiChart: www.hcvguidelines.org https://play.google.com/store/apps/details?id=com.liverpool • EASL:http://www.easl.eu/research/ourͲ uni.icharthep – HCVdrugͲdruginteractions:www.hepͲdruginteractions.org contributions/clinicalͲpracticeͲguidelines • TorontoGeneralHospital’sHCVdrugͲdrug interactiontables&news:www.hcvdruginfo.ca/ • Packageinserts Selecting&RefiningHCVTreatmentOptions Patientsbeing consideredfor HCVtherapy DetermineallpossibleDAAoptionsbasedongenotype,presenceof cirrhosis,treatmentͲnaïveorͲexperienced,&drugresistance Reviewallprescription&OTCmeds &herbalsupplements Screenforinteractionsusingresources &packageinserts RefineDAAoptionsbasedoninteractions, 2newARVs(bictegravir & doravirine):limiteddataforBICbutlookscompatiblewithallDAAs. priorAEs,&patientpreferences DORiscompatiblewithallDAAs. https://www.hcvguidelines.org/uniqueͲpopulations/hivͲhcv QuickDAARecap Case#1 Brand Generic MOA Gt HD Decomp. EFV/ PI/r /c Cirrhosis ETR A52yearͲoldAfricanAmericanwomancomes Epclusa sofosbuvir (SOF)+ NS5Binhibitor+ 1,2,3, яя inforherappointmentwiththeclinical velpatasvir (VEL) NS5Ainhibitor 4,5,6 Harvoni sofosbuvir (SOF)+ NS5Binhibitor+ 1,4,5, pharmacisttostartSOF/VEL(Epclusa). яяя ledipasvir (LDV) NS5Ainhibitor 6 Mavyret glecaprevir (GLE)+ NS3/4Aproteaseinhibitor+ 1,2,3, • HCV:TxͲnaïve,Gt1a,stage2fibrosis,no я CTPͲA(я) pibrentasvir (PIB) NS5Ainhibitor 4,5,6 cirrhosis(APRI=0.3),HCVVL=10million Vosevi sofosbuvir (SOF)+ NS5Binhibitor+ 1,2,3, velpatasvir (VEL)+ NS5Ainhibitor+ 4,5,6 CTPͲA(DRV) • Labs:Normalliverfunction,CrCl=75 voxilaprevir (VOX) NS3/4Aproteaseinhibitor • Meds: Zepatier elbasvir (EBR)+ NS5Ainhibitor+ 1,4 я CTPͲA grazoprevir (GZR) NS3/4Aproteaseinhibitor – TDF/FTC/EFV:1tabletonceͲdaily – Omeprazole:20mgonceͲdaily Case#1Recommended Question#1:WhichARVshaveamajor TreatmentOptions: drugͲdruginteractionwithSOF/VEL TxͲNaïve,HCVGt1a,notcirrhotic (Epclusa)? Regimens Dose Duration a. Efavirenz EBR/GZR* QDfixedͲdosecomboEBR(50mg)/GZR (100mg) x12weeks b. Darunavir/r GLE/PIB QDfixedͲdosecomboGLE(300mg)/PIB (120mg) x8 weeks SOF/LDV** QDfixedͲdosecomboSOF(400mg)/LDV(90mg) x12weeks c. Tenofoviralafenamide SOF/VEL QDfixedͲdosecomboSOF(400mg)/VEL(100mg) x12weeks d. Elvitegravir/c *IfnobaselineNS5ARAVsdetected(forEBR) e. Alloftheabove **x8weeksifHCVVL<6million,nonͲblack,HIVseronegative MechanismofSOF/VEL SOF/VEL(Epclusa)ͲARVInteractions (Epclusa) DrugͲDrugInteractions • SOF:substrateforPͲgp &BCRP DrugClass DrugName Recommendation VEL:substrateforPͲgp,BCRP,OATP,CYP3A4, NNRTIs RPV,DOR Nodoseadjustmentsneeded CYP2C8,&CYP2B6 EFV,ETR Notrecommended • InducersofPͲgp,CYP2B6,CYP2C8,orCYP3A4(e.g., PIs DRV/r/c, ATV/r/c,LPV/r Nodoseadjustmentsneeded rifampin,St.John’swort,EFV)љplasma InSTI RAL Nodoseadjustmentsneeded concentrationsofSOForVEL – Notrecommended EVG/c Nodoseadjustmentsneeded • VELisinhibitorofPͲgp,BCRP,&OATP DTG Nodoseadjustmentsneeded – CoͲadministrationofsubstratesofthesetransporters BIC Nodoseadjustmentsneeded mayјexposureofsuchdrugs N(t)RTI TDF/FTCorTAF/FTC Nodoseadjustmentsneeded – SubstrateofCYP3A4 ABC/3TC Nodoseadjustmentsneeded Case#1:Options 1. ChangeARTtononͲEFVͲcontainingregimen compatiblewithSOF/VEL (e.g.,DTGͲ,BICͲ,orRPVͲbased) OR 2. ChangeDAA – EBR/GZR&GLE/PIB (substratesofCYP3A&PͲ gp):incompatiblewithEFV – ConsiderSOF/LDV(Harvoni)x12weeks: compatible withEFV x12weeks:patientisAfricanAmerican,livingwithHIV,& HCVRNA>6million https://www.hcvguidelines.org/uniqueͲpopulations/hivͲhcv Case#1:OTCInteractions Question#2:Whatshouldyoutell heraboutomeprazole? • 52y/owoman,txͲnaïve,Gt1a,nocirrhosis, CrCl=75 a. Nothing • ChangeARTtoABC/3TC/DTG b. Trytoavoidacidblockersbut,ifyoumust, • Monitorforsideeffects&continuedHIVVL suppressionfor1Ͳ2monthsbeforestartingDAAs takeSOF/VELwithfood&4hoursbeforeOMP • 6weekslater… c. Trytoavoidacidblockersbut,ifyoumust, • ReadytostartSOF/VEL(Epclusa) takeOMP40mgoncedaily • YouaskheraboutanyOTCs&sheremindsyou d. TakefamotidineorantacidsinsteadofOMP, thatsheistakingomeprazole20mgoncedaily givenlackofinteractions forreflux VELͲOMPInteraction Case#1:AcidBlockersandPPIs SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX • јpHresultsinљVELsolubility&љVEL Antacids Separateby4hrs Separateby4hrs Separateby4hrs concentration H2RA Togetheror12hrs Togetheror12hrs Togetheror12hrs apart;FAM40mgBID apart;FAM40mgBID apart;FAM40mgBID • PPIs TogetherwithOMP Withfood,4hrs Canusewith OMP20 Trytoavoidacidblockersaltogether… 20mg beforeOMP20mg mg – PPIs:SOF/VELwithfood&4hrs beforePPI(atmax NostatisticallysignificantdifferenceinSVR12betweenhigh&lowPPI dosecomparabletoomeprazole20mg) doseswithGLE/PIBacrossgenotypes; reasonabletoavoidhighdose – H2ͲRAs:Givensimultaneouslywithor12hours PPIifpossible apartfromSOF/VELatчfamotidine40mgBID – Antacid:Separateby4hours Flamm S,etal.WorldCongressofGastroenterologyatACG2017;2017;Orlando,FL.P1435. Case#1:Conclusion Case#2 • Pt’sARTchangedtoABC/3TC/DTG A45yearͲoldmalepatientisbeingseenat – Monitoredfor6weekstoensuretolerating theclinicalpharmacyofficetogetstarted &HIVRNAsuppressed onGLE/PIB(Mavyret). • StartsSOF/VEL(Epclusa)&attains • HCV:TxͲnaïve,Gt1b,cirrhotic(ChildͲPugh Reminder: SVR12 scoreA) GLE/PIBcan’tbe • usedin – StoppedPPIwhenstartingSOF/VEL&able Meds:DRV/c/TAF/FTC,rosuvastatin decompensated cirrhosis(i.e., tocontrolGERDwithPRNfamotidine ChildͲPughB/C) Case#2Recommended Question#4:WithwhichARVis TreatmentOptions: GLE/PIB(Mavyret)compatible? TxͲnaïve,HCVGt1b,compensatedcirrhosis Regimens Dose Duration a. ATV/rorDRV/r GLE/PIB QDfixedͲdosecomboGLE (300mg)/PIB(120mg) x12weeks b. ELV/c EBR/GZR QDfixedͲdosecomboEBR(50mg)/GZR (100mg) x12weeks c. EFVorETR SOF/LDV QDfixedͲdosecomboSOF(400mg)/LDV(90mg) x12weeks SOF/VEL QDfixedͲdosecomboSOF(400mg)/VEL(100mg) x12weeks d. RAL,DTGorBIC e. Alloftheabove Question#4:WithwhichARVis EffectofInhibitorsonGLE/PIB(Mavyret) GLE/PIB(Mavyret)compatible? a. ATV/rorDRV/r GLE/PIBјELV/cCmax by 36%,AUCby47%. b. ELV/c GLECmax &AUC2.5Ͳ & 3.1Ͳfoldhigher, c. EFVorETR respectively,vs.GLE/PIB alone;PIBAUC57% higher. • GLE/PIBcontraindicatedwithATV/r/c d. RAL,DTGorBIC Noclinicallysignificant interactions,butcaution • GLE/PIBmaybeokaywithDRV/r&LPV/rbutnot e. Alloftheabove whenusingtogether.Very recommendedduetolackofclinicaldata limitedclinicaldata. • ELV/cleadstoelevatedGLE/PIB levelsbutmaybe usedwithcaution GLE/PIB(Mavyret)ͲARVInteractions Case#2:Statin&HCVDAAs • GLE/PIB(Mavyret)inhibitBCRP,PͲgp,OATP DrugClass DrugName Recommendation – Rosuvastatin (substrateofBCRP&OATP) NNRTIs RPV,DOR Nodoseadjustmentsneeded • Cmax ј5.6x,AUCј2.2x EFV,ETR Notrecommended • Donotexceed10mg/d PIs ATV/r Notrecommended – Pravastatin:reduceddoseby50% DRV/r,LPV/r Notrecommended(yet) – Atorvastatin:donotcoͲadminister InSTI RAL,DTG Nodoseadjustmentsneeded SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX BIC Nodata;probably ok Atorvastatin ND ND ч20mg Lowestdose Pitavastatin ND ND Lowestdose ELV/c Caution Pravastatin љdoseby50% ч40mg N(t)RTI TDF, TAF Nodoseadjustmentsneeded Rosuvastatin ч10mg ч10mg ч10mg Simvastatin Lowestdose Lowestdose SideNote:Warfarin SideNote:Antiplatelet&DOACs • UpdatedSOF,SOF/LDV,SOF/VEL,SOF/VEL/VOX: • Limiteddata “FluctuationsinINRvaluesmayoccurinpatients • LimitedabilitytomonitorpatientsonDOACSwith receivingwarfarinconcomitantwithHCVtreatment... FrequentmonitoringofINRvaluesisrecommended clinicallyavailablelabassays duringtreatmentandpostͲtreatment...” • Interactionmoresignificantwithribavirin&PrOD SOF/LDV SOF/VEL EBR/GZR GLE/PIB SOF/VEL/VOX Clopidogrel Caution Caution • Interactionusually resultsinљINR,needingјWarfarin Ticagrelor dose (ш15%) Dabigatran 2hrapart 2hrapart • MechanismunclearbuteradicationofHCVimprovesliver Edoxaban ND ND ND ND functiontoincreaseclottingfactorsynthesis&/or Apixaban ND ND ND ND warfarinmetabolism Rivaroxaban Caution Caution Caution Caution Case#2:Options Case#2:Conclusion 45y/omanstartingGLE/PIB(Mavyret).Gt1b, • cirrhotic,txͲnaïve;DRV/c/TAF/FTC,rosuvastatin. DuetoinsurancecoverageofGLE/PIB (Mavyret),wedecidetochangeARTto 1. ChangeART DTG/ABC/3TC. – Suggestions:DTGͲ,BICͲ orRPVͲbased – MonitorHIVVLx1Ͳ2monthsonnewARTbefore or startingDAAs 2. ChangeDAA • Reducerosuvastatin doseto10mg. – SOF/LDVx12weeks • StartGLE/PIB. – SOF/VELx12weeks Case#3 Question#5:WhichDAAagentsareokayto useinthosewitheGFR<30mL/min? You’reseeinga58yearͲoldWhitemaleon hemodialysiswhowouldliketostartHCV 1. EBR/GZR(Zepatier) treatment.Providerisnotsurewhattouse 2. GLE/PIB(Mavyret) givenpatient’srenalfunction. 3. SOF/LDV(Harvoni) – HCV:TxͲnaïve,Gt3,nocirrhosis 4. SOF/VEL(Epclusa) – Meds:DTG+ABC+3TC(renallyͲdosed) 5. 1&2 6. Alloftheabove Case#3 TreatmentOptions: Case#3GeneralOptions: RenalImpairment TxͲNaïve,Gt3,nocirrhosis CKD DAA Nodoseadjustment Duration 1Ͳ3EBR/GZRQDEBR(50mg)/GZR (100mg) x12weeks Regimens Dose Duration GLE/PIB QDGLE(300mg)/PIB (120mg) X8Ͳ16 weeks SOF/LDV QDSOF(400mg)/LDV(90mg) x12weeks SOF/VEL QDfixedͲdosecomboSOF x12weeks SOF/VEL QDSOF(400mg)/VEL(100mg) x12weeks (400mg)/VEL(100mg) DCV+SOF QDDCV(60mg**)+SOF(400mg) x12weeks GLE/PIB QDfixedͲdosecomboGLE x8weeks SMV+SOF QDSMV(150mg)+SOF(400mg) x12weeks (300mg)/PIB(120mg) SOF/VEL/VOX QDSOF(400mg)/VEL(100mg)/VOX (100mg) x12weeks 4Ͳ5 EBR/GZR QDEBR(50mg)/GZR (100mg) x12weeks GLE/PIB QDGLE(300mg)/PIB (120mg) X8Ͳ16 weeks ChronicKidneyDisease(CKD)stages: 1=normal(eGFR >90mL/min);2=mildCKD(eGFR 60Ͳ89mL/min);3=moderateCKD(eGFR 30Ͳ59ml/min) 4=severeCKD(eGFR 15Ͳ29mL/min);5=endͲstageCKD(eGFR <15mL/min) Case#3:Conclusion ImportantPoints • HeinitiatesGLE/PIB(Mavyret) • OnlySOF/LDV(Harvoni)canbeusedwithEFVorETR. • SOF/LDV&SOF/VEL(Epclusa)canbeusedwithPI/r& • Hedoesverywell&hasSVRpostͲ EVG/c. treatment • EBR/GZR(Zepatier)&GLE/PIB(Mavyret)okaywithPPIs. • PravastatinseemsokaywithmostDAAs. • EBR/GZR&GLE/PIBcanbeusedinESRD. • SOF/VEL&SOF/LDVcanbeusedindecompensated cirrhosis(treatinconsultationwithaliverspecialist) – GLE/PIB,EBR/GZR,&SOF/VEL/VOX(Vosevi)should not beusedinthosewithChildͲPughB&C. Acknowledgements • AnnieLuetkemeyer,MD • MegNewman,MD,FACP • DianeV.Havlir,MD SSTI:epidemiology y From1993–2005visitstoemergencydepartmentsfor SSTIsincreasedsubstantially y CoincidedwithriseincommunityMRSA y From2009–2014visitstoEDsforSSTIdecreased significantly TheMedicalManagementofHIV/AIDSandHepatitis y 8%declineinrateoverall(expressedperEDencounters) y 14.6%declineinrateamongpersonslivingwithHIV LisaWinston,MD y Adjustedrateratio1.9comparedwiththosewithoutHIV DivisionofHIV,ID,andGlobalMedicine ZuckerbergSanFranciscoGeneral/ UniversityofCalifornia,SanFrancisco Clin InfectDis2018; https://doi.org/10.1093/cid/ciy509 SSTI:epidemiology y RecurrentSSTIinPLWHiscommon Recentclinicaltrialsthathave y InasmallcohortofPLWHwithSSTIatasingleU.S. medicalcenter changedmanagementof y Estimatedriskofrecurrenceat1year:30% uncomplicatedcellulitis y Estimatedriskofrecurrenceat3years:47% y LowCD4countwasnotariskfactorforrecurrence BMCInfectDis2015; 10.1186/s12879Ǧ015Ǧ1216Ǧ1 Clindamycinvs.tmp/smx for uncomplicatedskininfections 280patientshad 95 cellulitiswithout abscess P=0.32 90 Visit Cure 85 Ǧ P=0.38 of Ǧ 80 Clindamycin Test Tmp/smx at 75 Cured 70 % 65 Intentiontotreat Abletoevaluate NewEngl JMed2015;372:1093Ǧ1103 Cephalexinvs.cephalexin+tmp/smx in patientswithuncomplicatedcellulitis 100.0% 82.0% 85.0% Cephalexin N=146 JAMA2017;317:2088Ǧ96 80.0% Cephalexin+ 60.0% tmp/smx 53.0% 49.0% 40.0% 20.0% 6.8% 6.8% 0.0% Cure Progressionto AdverseEvents • 496outpatientsolderthan12yearsseeninEDwithcellulitiswithoutabscess abscess Clin InfectDis2013; 56:1754Ǧ1762 Recentclinicaltrialsthathave changedthemanagementof uncomplicatedabscesses 2016;374:823Ǧ32 Significantsecondaryendpointsinperprotocolpopulation favoringtmpǦsmx overplacebo: • Subsequentsurgicaldrainage:3.4%vs.6.8% • Skininfectionsatnewsites:3.1%vs.10.3% NEJM2017;376:2545Ǧ55 • Infectionsinhouseholdmembers:1.7%vs.4.1% y Randomized786adultsandchildrenwithuncomplicated skinabscess y Lessthan5cminadults Abscesses:I&Dplusantibioticvs.I&Dalone y S.aureusisolatedfrom67% y 74%ofS.aureuswereMRSA y AfterI&D,randomizedtoclindamycin,tmpǦsmx,or y Benefitstoantibiotics placebo y Highercurerates y Curerates y Decreaseinnewskininfections(shortǦterm) y Clindamycin83.1% y Possiblelowerrateofsubsequentsurgicaldrainageand y TmpǦsmx 81.7% decreasedinfectionsinhouseholdmembers y Bothstatisticallydifferentfromplacebo,68.9% y Adverseevents(allresolved)morecommonwith clindamycin,noC.difficile;curerateswithclindamycinlower y ?Durationofantibiotictherapy forclindamycinǦresistantorganisms y Talanstudy–7days y Newinfectionsat1monthlesscommonwithclindamycin (6.8%)comparedwithtmpǦsmx (13.5%)orplacebo(12.4%) y Daum study–10days y Wouldshorterdurationbesufficient? NEJM2017;376:2545Ǧ55 NewlongͲactingIVdrugsfor skin andsofttissueinfections–active againstMRSA What’snewwithC.difficile? y Dalbavancin – about$3300foronedose y Oritavancin – about$3000foronedose Newname!!! Clostridioides difficile C.difficile infection(CDI) y HIVmaybeamodestriskfactorforCDI y Notclearifindependentvs.e.g.increaseduseof antibiotics y Noevidencethattreatmentshouldbemodifiedin PLWH • Metronidazolenolongerrecommended • Preferreddiagnostictesting • Roleoffecalmicrobiotatransplant(FMT) CDItreatmentrecommendation Preferreddiagnostictesting y Vancomycin(125mgPO4timesperday)or fidaxomicin (200mgPOtwicedaily)recommendedas y Concernsaboutnucleicacidamplificationtesting initialtherapyovermetronidazole,evenwhendiseaseis (NAAT)alonebeingtoosensitive,detecting notsevere colonizationwithoutdisease y Higherratesofclinicalcure/clinicalresponse y Recommendedtesting y 10Ǧdaycourseisstandard y StooltoxintestaspartofamultiǦstepalgorithm y Fulminantdisease:oralvancomycinisthetreatmentof y IfusingNAATalone choice y Onlysubmitspecimensifunexplaineddiarrheawithatleast3 y Fulminantdiseasewithileus: unformedstoolsin24hours y Vancomycin500mgPO4timesperdayPLUS y Donotsendspecimensfrompersonsreceivinglaxatives y Vancomycinasaretentionenemaq6hoursPLUS y IVmetronidazole RoleofFMTintreatmentof recurrentCDI FMTandimmunocompromise y Immunocompetentpatients y Recommendedforthosewithmultiplerecurrences(at y Shorttermsafetyappearsgood leasttwo) y Longtermrisksunknown y Wellacceptedbypatients y Relativelyfewreportstodateinimmunocompromised y Strongrecommendation,moderatequalityevidence patients y Observationalreportshavesomewhathighersuccessrates thanrandomizedtrials y OnlyafewinHIV/AIDS y Safeintheshortterm y FlaresreportedafterFMTinpatientswithinflammatory y Stoolcanbegivenbynasogastrictube,colonoscopy, boweldisease enema,orascapsules y Otherwise,particularcomplications,includinginfectious,not yetidentified JInfectChemother 2015;21:230Ǧ7 Zostervaccinerecombinant, adjuvanted (SHINGRIX) NEJM 2015;372:2087-96 • Phase 3 study; 7698 received vaccine, 7713 placebo • Adults 50 and older stratified by age • Two dose series • 6 cases zoster in vaccine group, 210 in placebo group • Mean follow up 3.2 years • 97% efficacy • No difference in efficacy by age • Mild-moderate systemic and local reactions common ZosterVaccineRecombinant(SHINGRIX) y FDAapproved10/20/17 y ContainrecombinantglycoproteinEplusanovel adjuvant(AS01B) y • 13,900 participants age 70 and older Givenastwodoses,2to6monthsapart • 2 doses adjuvanted subunit vaccine or placebo y Recommendedasaroutinevaccineforages50andolder • Follow up 3.7 years y Stillgiveifhistoryofzoster • Vaccine efficacy against zoster 89.8% y RevaccinatethosewhoreceivedZostavax – hasbeen • 23 cases vaccinated vs. 223 cases placebo studiedafter5years,waitatleast2months • No difference in efficacy by age y Noneedtoscreenforhistoryofchickenpoxortodo • More injection site and systemic reactions with vaccine laboratorytesting • Serious adverse events similar • Long-term follow up both studies in progress ZosterVaccineRecombinant(SHINGRIX) ZosterinPLWH y Indicatedwithchronicmedicalconditionsandlowdose immunosuppressivetherapy,e.g.<20mgprednisone y IncreasedriskwithlowerCD4countandhigher y Nocurrentrecommendationsforotherimmunocompromise viralload –pendingdata y Shortageduetohighdemand y IncreasedriskcomparedtothosewithoutHIV y Sideeffects:adverseevents(AEs)arecommon y RelativeriskhasdeclinedinARTera y Mostpeople(78%)havesomepainatinjectionsite y Estimated3–4fold(onestudy4–11fold)increasedrisk y SystemicAEsincludemyalgia,fatigue,headache,andfever y Higherrelativeriskatyoungerages y 1in6peoplehaveAEsthatinterferewithdailyactivities y SomewhatfewerAEsinthose70andolder BMCInfectDis2013;372doi:10.1186/1471Ǧ2334Ǧ13Ǧ372 https://www.cdc.gov/vaccines/vpd/shingles/hcp/shingrix/recommendations.html Clin InfectDis2015;60:1269Ǧ77 https://www.cdc.gov/mmwr/volumes/67/wr/mm6703a5.htm Zostervaccinerecombinant: IDWeek October2018:Immunogenicity,SafetyandPostͲhoc EfficacyAssessmentoftheAdjuvanted RecombinantZoster immuneresponsestudiedinPLWH VaccineinAdultswithHematologicMalignancies:APhase3, y Phase1/2randomized,placebocontrolledstudy RandomizedClinicalTrial evaluatingimmunogenicityandsafety y 562participantswithahematologicmalignancy y 74PLWHreceivedzostervaccine,mostonARTwith y Randomizedtoreceive2dosesRZVvs.placebo1Ǧ2 highCD4count monthsapart y Vaccinegivenas3dosesat0,2,and6months y 10daysbeforeor10daysafteracancertherapycycleor y Cellmediatedandhumoralimmuneresponseswere upto6monthsaftertherapycompletion demonstratedcomparedwithplacebo y Vaccinewasimmunogenic(datareportedIDWeek y Adverseeffectsweresimilartothoseseeninpersons 2017) withoutHIV Oralabstract149,studyconductedbyGSK JInfectDis2015;211:1279Ǧ87 Immunogenicity,SafetyandPostͲhocEfficacyAssessmentofthe Adjuvanted RecombinantZosterVaccineinAdultswith HematologicMalignancies:APhase3,RandomizedClinicalTrial *5.5%ofsubjectsintheplacebogrouphadzosteroverabout 1yearoffollowup % " ! ! # % $$ # )$(&') % ! $ %%$ %% % ! $ # ! 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h^d^ʹ ^ĞdžtŽƌŬĂŶĚ h^d^Ͳ ,ŽƵƐŝŶŐ hŶĚĞƌŐƌŽƵŶĚ ĐŽŶŽŵLJ ϯϬйƌĞƉŽƌƚŚŽŵĞůĞƐƐŶĞƐƐĂƚůĞĂƐƚŽŶĐĞŝŶƉĂƐƚ ϮϬйŚĂǀĞƉĂƌƚŝĐŝƉĂƚĞĚŝŶƵŶĚĞƌŐƌŽƵŶĚ ± ϭϮйŝŶůĂƐƚLJĞĂƌ ĞĐŽŶŽŵLJ ± ϴϲйƌĞƉŽƌƚĞĚŵŝƐƚƌĞĂƚŵĞŶƚďLJƉŽůŝĐĞ ± ϳϳй/Ws ϮϲйĂǀŽŝĚĞĚĂƐŚĞůƚĞƌĚƵĞƚŽĨĞĂƌŽĨďĞŝŶŐ ± ϳϮйƐĞdžƵĂůůLJĂƐƐĂƵůƚĞĚ ŵŝƐƚƌĞĂƚĞĚĚƵĞƚŽƚƌĂŶƐƐƚĂƚƵƐ ϯϯйŽĨĂůůůĂĐŬƚƌĂŶƐŐĞŶĚĞƌǁŽŵĞŶĂŶĚϯϬй ϳϬйŽĨƚŚŽƐĞǁŚŽƐƚĂLJĞĚŝŶĂƐŚĞůƚĞƌ ŽĨĂůůŵƵůƚŝƌĂĐŝĂůƚƌĂŶƐŐĞŶĚĞƌǁŽŵĞŶƌĞƉŽƌƚ ĞdžƉĞƌŝĞŶĐĞĚƚƌĂŶƐͲƌĞůĂƚĞĚĚŝƐĐƌŝŵŝŶĂƚŝŽŶ ƉŽůŝĐĞĂƐƐƵŵŝŶŐƚŚĞLJǁĞƌĞƐĞdžǁŽƌŬĞƌƐ h^d^ʹ ,ĂƌĂƐƐŵĞŶƚĂŶĚsŝŽůĞŶĐĞ ,/sͲ ƉŝĚĞŵŝŽůŽŐLJ ϱϰйůŝĨĞƚŝŵĞ/Ws ϰϳйůŝĨĞƚŝŵĞƐĞdžƵĂůĂƐƐĂƵůƚ͕ϭϬйŝŶůĂƐƚLJĞĂƌ ϰϲйǀĞƌďĂůůLJŚĂƌĂƐƐĞĚŝŶƉĂƐƚLJĞĂƌ ϱϵйĂǀŽŝĚĞĚĂƉƵďůŝĐƌĞƐƚƌŽŽŵŝŶƉĂƐƚLJĞĂƌ ± ϯϮйůŝŵŝƚĞĚĨŽŽĚĂŶĚĚƌŝŶŬƚŽĂǀŽŝĚŶĞĞĚĨŽƌƌĞƐƚƌŽŽŵ ± ϴйƌĞƉŽƌƚƌĞƐƵůƚŝŶŐhd/ŽƌŬŝĚŶĞLJƉƌŽďůĞŵŝŶƉĂƐƚLJĞĂƌ ϱ ϭϭͬϮϴͬϮϬϭϴ dƌĂŶƐŐĞŶĚĞƌĚƵůƚƐĂŶĚĚŽůĞƐĐĞŶƚƐ^ĞƌǀĞĚďLJ &ĂĐƚŽƌƐǁŚŝĐŚŝŵƉĂĐƚ,/sƌŝƐŬƐĂŶĚ Zt,WZĞƚĞŶƚŝŽŶŝŶ ŽƵƚĐŽŵĞƐŝŶƚƌĂŶƐŐĞŶĚĞƌƉŽƉƵůĂƚŝŽŶƐ ĂƌĞĂŶĚsŝƌĂů^ƵƉƉƌĞƐƐŝŽŶ͕ϮϬϭϲ ϭϬϬ ϭϬϬ sŝƌĂů ŝƐĐƌŝŵŝŶĂƚŝŽŶ ZĞƚĞŶƚŝŽŶŝŶ ^ƵƉƉƌĞƐƐŝŽŶ ĂƌĞ ŵŽƚŝŽŶĂůĂŶĚƉŚLJƐŝĐĂůƚƌĂƵŵĂ ϴϰ͘ϵ ϴϭ͘ϳ ϳϵ͘ϴ ϳϵ͘Ϭ hŶƐƚĂďůĞŚŽƵƐŝŶŐ ϴϬ ϴϬ WĞƌĐĞŶƚ ϳϱ͘Ϯ ϳϰ͘ϴ WĞƌĐĞŶƚ >ĂĐŬŽĨĞŵƉůŽLJŵĞŶƚƉƌŽƚĞĐƚŝŽŶƐͬŽƉƚŝŽŶƐ ϳϬ͘ϴ ϳϮ͘Ϭ ± WŽǀĞƌƚLJ >ĂĐŬŽĨŐĞŶĞƌĂůůĞŐĂůƉƌŽƚĞĐƚŝŽŶƐ ϲϬ ϲϬ ,ŝŐŚƌĂƚĞƐŽĨŝŶĐĂƌĐĞƌĂƚŝŽŶ ± ^ƵƌǀŝǀĂůƐĞdžǁŽƌŬ WŽƚĞĂƚ ĞƚĂů͖>ĂŶĐĞƚ͖:ĂŶϭϳ͖ϯϴϱ;ϵϵϲϰͿ͗ϮϳϰͲϴϲ ŚƚƚƉƐ͗ͬͬŚĂď͘ŚƌƐĂ͘ŐŽǀͬƐŝƚĞƐͬĚĞĨĂƵůƚͬĨŝůĞƐͬŚĂďͬĚĂƚĂͬĚĂƚĂƌĞƉŽƌƚƐͬZt,WͲĂŶŶƵĂůͲ ĐůŝĞŶƚͲůĞǀĞůͲĚĂƚĂͲƌĞƉŽƌƚͲϮϬϭϲ͘ƉĚĨ ΎZLJĂŶtŚŝƚĞ,/sͬ/^WƌŽŐƌĂŵĐůŝĞŶƚƐ;ŶŽŶͲWͿ͕ďLJƌĂĐĞͬĞƚŚŶŝĐŝƚLJĂŶĚ ϲ ϭϭͬϮϴͬϮϬϭϴ ϳϴйƚƌĂŶƐŐĞŶĚĞƌǁŽŵĞŶƌĞƚĂŝŶĞĚŝŶĐĂƌĞǀƐ ϴϬйŶĂƚŝŽŶĂůĂǀĞƌĂŐĞ ϳϰйǀŝƌŽůŽŐŝĐ ƐƵƉƉƌĞƐƐŝŽŶǀƐ ϴϭйŶĂƚŝŽŶĂů ĂǀĞƌĂŐĞ ,/sŝŶƚƌĂŶƐŐĞŶĚĞƌŵĞŶ sĞƌLJůŝƚƚůĞŝƐŬŶŽǁŶ͕ůŝƚƚůĞĚĂƚĂ DŽƐƚ,/sƌĞƐĞĂƌĐŚŝŶƚƌĂŶƐŐĞŶĚĞƌƉŽƉƵůĂƚŝŽŶƐ ŝƐŽƌŝĞŶƚĞĚƚŽǁĂƌĚƐƚƌĂŶƐŐĞŶĚĞƌǁŽŵĞŶ ϳ ϭϭͬϮϴͬϮϬϭϴ ,/sƐĐƌĞĞŶŝŶŐĂŶĚƌŝƐŬĂƐƐĞƐƐŵĞŶƚ ĨĨĞĐƚŝǀĞƌŝƐŬĂƐƐĞƐƐŵĞŶƚƌĞƋƵŝƌĞƐĂďŝůŝƚLJƚŽ ĂŶĚĐŽŵĨŽƌƚǁŝƚŚŽďƚĂŝŶŝŶŐĂŶĂĐĐƵƌĂƚĞƐĞdžƵĂů ŚŝƐƚŽƌLJ ± DƵƐƚďĞĐŽŶĚƵĐƚĞĚŝŶĂĐƵůƚƵƌĂůůLJĂƉƉƌŽƉƌŝĂƚĞ ŵĂŶŶĞƌ hƐĞŽƉĞŶĞŶĚĞĚƋƵĞƐƚŝŽŶƐƚŚĂƚĚŽŶŽƚŵĂŬĞ ĂƐƐƵŵƉƚŝŽŶƐ ± ^ŚŽƵůĚŝŶĐůƵĚĞĂŶĂƚŽŵLJͲƐƉĞĐŝĨŝĐƐĞdžƵĂůďĞŚĂǀŝŽƌ ŽŶ͛ƚũƵƐƚĂƐŬ͞ĚŽLJŽƵŚĂǀĞƐĞdž͍͕͟ĂƐŬƚŚĞŚŽǁ͛ƐĂŶĚ ǁŚĞƌĞ͛Ɛ͘WĞŶŝůĞͲĂŶĂů͍WĞŶŝůĞͲŽƌĂů͍/ŶƐĞƌƚŝǀĞ͍ ZĞĐĞƉƚŝǀĞ͍,ĂƐƉĂƚŝĞŶƚŚĂĚĂǀĂŐŝŶŽƉůĂƐƚLJ͍ ŶŐĂŐŝŶŐƚƌĂŶƐŐĞŶĚĞƌƉĞŽƉůĞŝŶ,/s ŶŐĂŐŝŶŐƚƌĂŶƐŐĞŶĚĞƌƉĞŽƉůĞŝŶ,/s ƉƌŽŐƌĂŵƐĂŶĚƐĞƌǀŝĐĞƐ ƉƌŽŐƌĂŵƐĂŶĚƐĞƌǀŝĐĞƐ;ĐŽŶƚŝŶƵĞĚͿ ,/sƉƌĞǀĞŶƚŝŽŶĂŶĚƚƌĞĂƚŵĞŶƚŝŶƚĞƌǀĞŶƚŝŽŶƐ dƌĂŶƐͲŝŶĐůƵƐŝǀĞƐŽĐŝĂůŵĂƌŬĞƚŝŶŐ ĂŶĚƉƌŽŐƌĂŵƐƐŚŽƵůĚďĞĚĞƐŝŐŶĞĚƐƉĞĐŝĨŝĐĂůůLJ ĚĚƌĞƐƐĐŽŵŵƵŶŝƚLJůĞǀĞůĐŽŶĐĞƌŶƐĂďŽƵƚ ĨŽƌƚƌĂŶƐŐĞŶĚĞƌƉŽƉƵůĂƚŝŽŶƐ͕ƌĂƚŚĞƌƚŚĂŶ ŝŶƚĞƌĂĐƚŝŽŶƐďĞƚǁĞĞŶ,/sŵĞĚŝĐĂƚŝŽŶƐĂŶĚ ĂŐŐƌĞŐĂƚĞĚǁŝƚŚ͕ŽƌĂĚĂƉƚĞĚĨƌŽŵD^DŽƌ ŐĞŶĚĞƌĂĨĨŝƌŵŝŶŐŚŽƌŵŽŶĞƐ ŽƚŚĞƌƉŽƉƵůĂƚŝŽŶƐ ŶƐƵƌĞƐĞƌǀŝĐĞƐĂƌĞĚĞůŝǀĞƌĞĚďLJĂƉƌŽǀŝĚĞƌ ± ĚĂƉƚĞĚŝŶƚĞƌǀĞŶƚŝŽŶƐĨĂŝůƚŽƚŽ ĂĚĚƌĞƐƐƵŶŝƋƵĞ ǁŚŽŝƐŬŶŽǁůĞĚŐĞĂďůĞŝŶƚƌĂŶƐŐĞŶĚĞƌŚĞĂůƚŚ ƐƚƌƵĐƚƵƌĂůĨĂĐƚŽƌƐ͕ŝŶĞƋƵŝƚŝĞƐ͕ĂŶĚďĂƌƌŝĞƌƐ ĞdžƉĞƌŝĞŶĐĞĚďLJƚƌĂŶƐŐĞŶĚĞƌƉĞŽƉůĞ ĂƌƌŝĞƌƐĂŶĚĨĂĐŝůŝƚĂƚŽƌƐƚŽĞŶŐĂŐĞŵĞŶƚĂŶĚƌĞƚĞŶƚŝŽŶŝŶĐĂƌĞĂŵŽŶŐ ƚƌĂŶƐŐĞŶĚĞƌǁŽŵĞŶůŝǀŝŶŐǁŝƚŚŚƵŵĂŶŝŵŵƵŶŽĚĞĨŝĐŝĞŶĐLJǀŝƌƵƐ͘ ^ĞǀĞůŝƵƐ :D͕WĂƚŽƵŚĂƐ ͕<ĞĂƚůĞLJ :'͕:ŽŚŶƐŽŶDK͘ŶŶĞŚĂǀ DĞĚ͘ ϮϬϭϰ &Ğď͖ϰϳ;ϭͿ͗ϱͲϭϲ ϴ ϭϭͬϮϴͬϮϬϭϴ ŝWƌ dž Zdʹ ƌĞƐƵůƚƐŽĨ ƚƌĂŶƐŐĞŶĚĞƌƐƵďĂŶĂůLJƐŝƐ /ŶƚĞŶƚŝŽŶƚŽƚƌĞĂƚ ± ϭϭƐĞƌŽĐŽŶǀĞƌƐŝŽŶƐ ŝŶƚŚĞŝŶƚĞƌǀĞŶƚŝŽŶŐƌŽƵƉǀƐ ϭϬŝŶƚŚĞ ƉůĂĐĞďŽŐƌŽƵƉ ƐƚƌĞĂƚĞĚ ± EŽŶĞŽĨƚŚĞd'tǁŚŽƐĞƌŽĐŽŶǀĞƌƚĞĚ ŚĂĚƉƌŽƚĞĐƚŝǀĞĚƌƵŐ ůĞǀĞůƐĂƚƚŚĞƚŝŵĞŽĨĚĞƚĞĐƚŝŽŶ ZĂŶĚŽŵĚƌƵŐůĞǀĞůƐ ± dƌĂŶƐŽƌǁŽŵĂŶ/ůĞƐƐůŝŬĞůLJƚŚĂŶD^DƚŽŚĂǀĞĂůǁĂLJƐ ĚĞƚĞĐƚĞĚ;WсϬ͘Ϭϰ͕KZсϬ͘ϯϵ͕ϵϱй/Ϭ͘ϭϲƚŽϬ͘ϵϲͿ ŝWƌ dž K> ʹ ZĞƐƵůƚƐŽĨ ŝWƌ dž K> ʹ ZĞƐƵůƚƐŽĨ ƚƌĂŶƐŐĞŶĚĞƌƐƵďĂŶĂůLJƐŝƐ ƚƌĂŶƐŐĞŶĚĞƌƐƵďĂŶĂůLJƐŝƐ ;ĐŽŶƚŝŶƵĞĚͿ ϭϲϬϯĞůŝŐŝďůĞ;ϭϵϮd'tͿ d'tƵƐŝŶŐŚŽƌŵŽŶĞƐůĞƐƐůŝŬĞůLJƚŽŚĂǀĞĂŶLJ;KZ Ϭ͘ϯϮ͕ƉсϬ͘ϬϬϮͿŽƌƉƌŽƚĞĐƚŝǀĞ;KZϬ͘ϭϰ͕WфϬ͘ϬϬϭͿ ϭϮϮϱƉĂƌƚŝĐŝƉĂƚĞĚ;ϭϱϭd'tͿ ĚƌƵŐůĞǀĞůƐĐŽŵƉĂƌĞĚƚŽd'tŶŽƚƵƐŝŶŐ ŚŽƌŵŽŶĞƐ Wƌ W ƵƉƚĂŬĞĐŽŵƉĂƌĂďůĞƚŽD^D ± ;ϳϵйǀƐ ϳϲй͕ƉсϬ͘ϰϱͿ d'tƵƐŝŶŐŚŽƌŵŽŶĞƐůĞƐƐůŝŬĞůLJƚŽŚĂǀĞĂŶLJ;KZ d'tůĞƐƐƚŝŵĞǁŝƚŚƉƌŽƚĞĐƚŝǀĞĚƌƵŐĐŽŶĐĞŶƚƌĂƚŝŽŶƐǀƐ D^D Ϭ͘ϰϭ͕ƉсϬ͘ϬϬϯͿŽƌƉƌŽƚĞĐƚŝǀĞ;KZϬ͘ϭϬ͕WфϬ͘ϬϬϭͿ ;ϭϳйǀƐ ϯϱй͕WфϬ͘ϬϬϭͿ ĚƌƵŐůĞǀĞůƐĐŽŵƉĂƌĞĚƚŽD^D ŵŽŶŐĂůůd't͕ƚƌĞŶĚƚŽǁĂƌĚĨĞǁĞƌŚĂǀŝŶŐĐŽŶĐĞŶƚƌĂƚŝŽŶƐ EŽĚŝĨĨĞƌĞŶĐĞďLJƵƐĞŽĨϭϳͲďĞƚĂĞƐƚƌĂĚŝŽů ǀƐ ŝŶĚŝĐĂƚŝŶŐхϯƚĂďůĞƚƐͬǁĞĞŬǀƐ D^D;KZͲϬ͘ϳϭ͕ϵϱй/Ϭ͘ϰϵ ƐLJŶƚŚĞƚŝĐĞƐƚƌŽŐĞŶƐ;ƉсϬ͘ϳϰͿ ƚŽϭ͘Ϭϯ͕ƉсϬ͘ϬϳͿ͘ ϵ ϭϭͬϮϴͬϮϬϭϴ ŝWƌ dž K> ʹ ƌĞƐƵůƚƐŽĨ ƚƌĂŶƐŐĞŶĚĞƌƐƵďĂŶĂůLJƐŝƐ ;ĐŽŶƚŝŶƵĞĚͿ Ϯd'tƐĞƌŽĐŽŶǀĞƌƐŝŽŶƐ ± ϭŚĂĚ^ďĞůŽǁůŝŵŝƚŽĨĚĞƚĞĐƚŝŽŶ 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1HHGDORWPRUHGDWD PresentedP by HIV,H ID and Global Medicine Division ZuckerbergZ San Francisco General Hospital and Trauma Center DepartmentD of Medicine, University of California SanS Francisco, School of Medicine