Faculty/Presenter Disclosure. HIV Update Outline. Undetectable = Untransmissable HTPN 052. Partner Opposites attract 9/28/2018

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1 Faculty/Presenter Disclosure HIV Update 2018 Dr. Joss de Wet Clinical Assistant Professor Family Medicine UBC Faculty: Joss de Wet Relationships with financial sponsors: Speakers Bureau/Honoraria: Gilead, ViiV, Merck. Advisory board/consulting Fees: Gilead, ViiV, Merck. Mitigating Potential Bias Discuss principles and not specific drugs Will discuss drugs by pharmaceutical names, use guidelines where appropriate and not discuss any off label use of products Outline Undetectable = Uninfectious How we get there How to follow Undetectable = Untransmissable HTPN 052 Partner Opposites attract HPTN 052: Immediate vs Delayed ART in Serodiscordant Couples HIV-infected, sexually active serodiscordant couples; CD4+ cell count of the infected partner: cells/mm 3 (N = 1763 couples) Immediate ART Initiate ART at CD4+ cell count cells/mm 3 (n = 886 couples) Delayed ART Initiate ART at CD4+ cell count 250 cells/mm 3 * (n = 877 couples) *Based on 2 consecutive values 250 cells/mm 3. Primary efficacy endpoint: virologically linked HIV transmission Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial infection and/or death Couples received intensive counseling on risk reduction and use of condoms DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up continues but all HIV-infected partners offered ART after release of results. Cohen MS, et al. N Engl J Med :3-505 August 11,

2 HPTN 052: HIV Transmission Reduced by 96% in Serodiscordant Couples Delayed Arm: 27 Linked Transmissions: 28 P <.001 Total HIV-1 Transmission Events: 39 (4 in immediate arm and 35 in delayed arm; P <.0001) Immediate Arm: 1 Cohen MS, et al. IAS Abstract MOAX0102. Cohen MS, et al. N Engl J Med :3-505 August 11, 2011 Unlinked or TBD Transmissions: 11 Single transmission in patient in immediate ART arm believed to have occurred close to time therapy began and prior to HIV-1 RNA suppression OPPOSITES ATTRACT STUDY International, prospective cohort study assessing the incidence of linked HIV transmission in MSM serodiscordant couples when HIV-infected partner on ART and virologically suppressed Australia, Brazil, Thailand N = 343 couple; 591 CYFU; 16,889 acts of CLAI (Condomless Anal intercourse) 95% HIV-infected partner HIV-1 RNA undetectable No linked infection 3 infections during study contracted from outside partners STI 17.5% during study, no HIV 30% Undetectable partners insertive Bavinton B et al. (presenter Grulich A) HIV treatment prevents HIV transmission in male serodiscordant couples in Australia, Thailand and Brazil. 9th International AIDS Society Conference on HIV Science, Paris, abstract no TUAC0506LB, July 2017 Opposites attract study PARTNER2: HIV Risk in Serodiscordant MSM Partners Multicenter, observational, prospective study of HIV serodiscordant couples in which the HIV-positive partners received suppressive ART 783 MSM couples contributed 15 PARTNER1: (MSM and heterosexuals) PARTNER2: (MSM only) Primary aim: estimate within-couple HIV transmission risk for serodiscordant MSM having condomless sex while HIVpositive partner had HIV-1 RNA < 200 copies/ml No PEP or PrEP use reported by HIV-negative partner Linked infections established by phylogenetic analysis of HIV-1 pol and env sequences isolated from plasma or PBMCs Rodger A, et al. AIDS Abstract WEAX0104LB. Slide credit: clinicaloptions.c PARTNER2: HIV Transmission No linked transmissions documented in ~ 77,000 condomless sex acts when HIV-positive MSM partner suppressed to HIV-1 RNA < 200 copies/ml Sexual Behavior Reported by HIV-Negative Partner Linked Transmissio ns, n Upper 95% CI* Condomles s Sex Acts, n CYFU Any sex Anal sex Insertive anal sex Receptive anal sex without ejaculation Receptive anal sex with ejaculation Any sex with an STI Unlinked transmissions occurred in 15 initially HIV-negative MSM partners Rodger A, et al. AIDS Abstract WEAX0104LB. Slide credit: clinicaloptions.c *For rate of within-couple HIV transmission per 100 CYFU. Compared with 0.84 for MSM and 0.46 for heterosexuals in PARTNER1. Undetectable = Uninfectious Dr Anthony Fauci, director of the US National Institute for Allergies and Infectious Diseases, said: Scientists never like to use the word Never for a possible risk. But I think in this case we can say that the risk of transmission from an HIV-positive person who takes treatment and has an undetectable viral load may be so low as to be unmeasurable, and that s equivalent to saying they are uninfectious. It s an unusual situation when the overwhelming evidence base in science allows us to be confident that what we are saying is. 2

3 HIV cascade of care BC 2017 State of affairs Initiate ART As Soon As Possible After HIV Diagnosis When to Start Antiretroviral Therapy IAS USA Recommendations 2018 Rapid start (including same day as diagnosis) ART, unless that patient is not ready to commit to starting therapy o Structural barriers should be removed Samples for HIV-1 RNA level; CD4 cell count; HIV genotype for NRTI, NNRTI, and PI; HLA-B*5701 testing; laboratory tests to exclude active viral hepatitis; and chemistries should be drawn before beginning ART, but treatment may be started before results are available. NNRTIs (possible transmitted resistance) and abacavir (without HLA-B*5701 results) should not be used for rapid ART start ART should be started as soon as possible (but within 2 weeks) after diagnosis of most opportunistic diseases Slide 17 of Slide 18 of 3

4 Recommended Initial Regimens: InSTI Plus 2 nrtis Recommended Initial Regimens IAS USA Recommendations 2018 Bictegravir/TAF/emtricitabine Dolutegravir/abacavir/lamivudine Dolutegravir plus TAF/emtricitabine Slide 19 of Slide 20 of 2018 IAS USA Antiretroviral Guidelines: Key Updates Recommend initial regimens focus primarily on unboosted (InSTI) regimens Encourage rapid initiation of ART, including same day initiation, if feasible Recommend against routine use of Mycobacterium avium complex prophylaxis for those with advanced disease on effective ART Recommended Initial Regimens: If an InSTI Is Not Available Darunavir/cobicistat/TAF (or TDF)/emtricitabine* Darunavir boosted with ritonavir plus TAF (or TDF)/emtricitabine Efavirenz/TDF/emtricitabine Elvitegravir/cobicistat/TAF (or TDF)/emtricitabine Raltegravir plus TAF (or TDF)/emtricitabine Rilpivirine/TAF (or TDF)/emtricitabine (if pretreatment HIV RNA level is <100,000 c/ml and CD4 cell count is >200/µL) Slide 21 of Slide 22 of * Fixed-dose D/c/TAF/FTC tablet approved July 2018 Recommended Laboratory Monitoring Recommended Laboratory Monitoring Once HIV RNA level is <50 c/ml, monitor every 3 months until virus is suppressed for at least a year. Then, monitoring can be reduced to every 6 months if the patient maintains adherence CD4 cell counts every 6 months until counts >250/μL for at least 1 year with concomitant viral suppression Age- and risk-appropriate screening for STIs at various anatomical sites, anal or cervical dysplasia, TB, general health, and medication toxicity is recommended Once a viral load is >50 c/ml, repeat test within 4 weeks and reassess for adherence and tolerability Measurement of viral load at 4 to 6 weeks after starting a new ART regimen is recommended Recommend discontinuation of routine CD4+ counts once a patient has sustained undetectable HIV RNA for a year and has a CD4+ count >250 cells/ul $225 per test Slide 23 of Slide 24 of 4

5 Percent uninfected 9/28/2018 Future Directions in ARVs Long-acting drugs Injectable formulations Implantable drugs Nanoparticles Viral vector delivery Vaccine Evaluation of lead HIV-1 vaccine regimen in : Phase 1/2a study testing heterologous prime boost regimens using mosaic Ad26 and MVA vectors combined with Env protein Hanneke Schuitemaker VP, Head Viral Vaccine Discovery and Translational Medicine, Janssen Vaccines and Prevention B.V. Professor in Virology at the Academic Medical Center, University of Amsterdam IAS Paris, 24 July 2017 Slide 25 of Goal: Global HIV-1 Prophylactic Vaccine Key elements The Ad26/Ad26+gp140 HIV Vaccine Regimen Provided Significant Protection Against SHIV SF162P3 Challenges in NHP (study 13-19*) Vectors that elicit optimal immune responses Mosaic inserts for global coverage (gag-pol-env) Trimeric Env proteins for improved immunity week post first challenge Ad boost gp140 boost Ad+gp140 boost MVA boost MVA+gp140 boost Sham *Statistically significant vs Sham in a Cox proportional hazard model and Log-rank test; Statistically significant vs Sham in a 2-sided Fisher s exact test 27 *Supported by IPCAVD grant 28 Aim: to develop a Prophylactic vaccine offering protection against all clades of HIV-1 through an heterologous prime boost regimen Studies that inform decision to proceed with a Phase 2b/Proof of Concept study Double Prime Double Boost Ad26.Mos4.HIV Ad26 vectors with Mosaic gag-pol or env inserts Ad26.Mos1.Gag-Pol Ad26.Mos2.Gag-Pol Ad26.Mos1.Env Ad26.Mos2S.Env Co-formulated 1:1:1:1 Ad26.Mos4.HIV Ad26 vectors with Mosaic gag-pol or env inserts Ad26.Mos1.Gag-Pol Ad26.Mos2.Gag-Pol Ad26.Mos1.Env Ad26.Mos2S.Env Co-formulated 1:1:1:1 gp140 Clade C Soluble trimeric gp140 Env protein with Alum + OR gp140 Clade C + Mosaic Soluble trimeric gp140 Env proteins with Alum Clade C + Mosaic NHP Study Efficacy / correlates Phase 2a Safety / Immuno Phase 2a Safety / Immuno Phase 2a TRAVERSE Safety / Immuno Start PoC Post 3 rd vacc Post 4 th vacc Post 2 nd and 3 rd vacc months Regimen to be selected after Phase 1/2a

6 From Phase 1/2a to Proof of Concept study pre-specified Go/no-Go criteria TRAVERSE Post 3rd Post 4th Go/No Go criteria towards Phase 2b/PoC based on Lead Regimen In order to move to a PoC efficacy study, the ELISA and ELISPOT criteria have to be met The ADCP criteria, Magnitudes and Env boost are considered supportive Selection of criteria based on: Immune correlates of protection identified in NHP studies Emphasis on: Vaccine take as demonstrated by humoral and cellular immune responses Magnitude of humoral and cellular immune responses Functionality of elicited antibodies 31 Criteria Endpoint Target (LL of 95% CI) Humoral Cellular Env boost Magnitude Results post 3 rd Results post 4 th IgG binding responses on Clade C Env >90% (>77%) 100% (93%) 100% (92%) ADCP responses to Clade C Env >56% (>40%) 72% (57%) 80% (65%) Elispot responses to at least one ENV peptide pool* IgG to clade C Env of Ad/Ad+Env over Ad/Ad >2.15 log10 cpte Env ELISPOT OR >3.8 log10 Clade C gp140 ELISA Subjects should be above BOTH response thresholds *PTE Env peptide pool >50% (>35%) 77% (62%) 83% (68%) >1.5 fold 5.5 fold (3.5) 6.9 fold (4.5) post 3 rd : post 4 th : >60% >75% post 3 rd : post 4 th : >40% >60% 94% 93% 64% 80% 32 HPX2008/HVTN 705 Design: Multicenter, randomized, parallel group, placebo-controlled, double-blind clinical trial Countries: South Africa, Zambia, Zimbabwe, Malawi, Mozambique Target N: 2,600 Population: Sexually active HIV-1 uninfected women (born female), age years N=2,600 Women 1:1 randomization Mo. 7 Wk 28 (PP infections) Vaccine 2nd stage (24-36) Placebo 2nd stage (24-36) Mo. 24 Wk years Mo. 36 Wk years Summary Undetectable = Untransmissable = Uninfectious Start HAART ASAP Integrase class is recommended Stop CD4 counts once fully suppressed Future directions 33 6