3 4 Disclosure I have received research grants awarded to my institution from Gilead Sciences, Inc. ntiretroviral medications have been provided by Gilead Sciences, Inc. Susan Little, M.D. Professor of Medicine University of California San Diego Rapid RT how early is early enough? Post-treatment control is it real? Using molecular epidemiology to interrupt transmissions during recent infection Rapid RT how early is early enough? Post-treatment control is it real? Using molecular epidemiology to interrupt transmissions during recent infection
5 7 8 How early is early enough?? Is there a critical time period following acute HIV infection during which RT is capable of restoring normal immune function? - Normal CD4 defined as 900 cells/mm 3 Rate of Recovery of CD4+ Counts Le T, et al. NEJM 2013 6 Le T, et al. NEJM 2013 Rate of Recovery of CD4+ Counts RT Start CD4+ 900 cells/mm 3 (% of participants) CD4+ Recovery to 900 cells/mm 3 CD4>500, RT>4 mo from EDI CD4>500, RT<4 mo from EDI CD4>500, RT>12 mo from EDI CD4<500, RT<4 mo from EDI CD4<500, RT>4 mo from EDI CD4<500, RT>12 mo from EDI Months since Initiation of RT Le T, et al. NEJM 2013
9 11 Conclusions The probability of attaining a CD4 >900 on RT was greatest for those who started RT within 4 months of EDI. Each month delay in RT reduced probability of achieving a CD4 > 900 by approximately 10%. Chance of achieving CD4>900 reduced by 94% if CD4<500 at RT start, independent of EDI. <25 % of RT-naïve patients maintained CD4 500 beyond 12 months. Modified RPID protocol: San Diego (2014-2016) Clinic-based cohort of consecutive patients with newly diagnosed HIV - Including HI, Early HIV, and chronic HIV (any CD4) Intervention: Modified RPID Program: 1) ccess to HIV provider within 24-48 hrs of HIV diagnosis 2) Same-day medical visit (2-4 hours) with safety and clinical care labs 3) RT Provided: elvitegravir, cobicistat, emtricitabine & tenofovir alafenamide 4) Telephone f/u within 14 days to review labs, review adherence, etc. 5) Case Management: insurance assessment and linkage to care RT Start: 194 (91%) Initiated RT - 146 (68.5%) within 7 days - Same day (34.7%); next day (11.3%); within 7d (22.5%) Le T, et al. NEJM 2013 10 Hoenigl M, et al. Scientific Reports 2016; Little, unpublished data RT Outcomes in EH Participants (<70d) Variable Universal RT Enrollment period 2009-2013 Modified RPID Jul 2014- Jun 2016 Jul 2016- Present N 162 38 38 Started RT; n (%) 111 (68.5) 35 (92.1) 36 (94.7) Presentation to RT; med days (IQR) 62 (34,142) 12 (8,20) 5 (1,8) Rapid RT how early is early enough? Post-treatment control is it real? Using molecular epidemiology to interrupt transmissions during recent infection EDI to RT; med days (IQR) 105 (66,180) 34 (22,79) 24 (17,75) RT to VL suppression; med days (IQR) 84 (30,169) 55 (28,98) 30 (27,84) Little, San Diego PIRC, unpublished data 12
13 15 Post-Treatment Control (PTC) PTC Pooled nalysis: 700 participants/14 studies PTCs identified from 14 clinical studies: - 8 CTG studies (371, 5024, 5068, 5102, 5130, 5170, 5187, and 5197) - Montreal Primary HIV Infection Cohort (Montreal PIC) - Seattle Primary Infection Program (SeaPIP) - UCSD Primary Infection Cohort (UCSD PIC) - UCSF OPTIONS study - NIH therapeutic vaccine trial (NIH) - Ragon HIV Controllers cohort (Ragon) Red=Early-treated lue=chronic-treated 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. lter G, et al. IS Global Scientific Strategy: towards an HIV cure 2016 14 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) Early-treated PTC vs. NC had slightly lower pre-rt VL (4.7 vs. 4.9 log 10 RN 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 Namazi, et al. JID 2018 16 Namazi, et al. JID 2018
17 19 CD4 Changes post TI (24 weeks) CD4+ levels generally preserved in PTC, but declined in NC after TI (-32 vs. -221 CD4+ cells/mm 3, P <.001) Similar findings in earlytreated and chronic-treated persons 90% 80% VL Changes post TI (24 weeks) The median VL peak was lower for PTCs than NCs (2.6 vs. 4.7 log 10 HIV RN copies/ml respectively, P <.001) Similar findings in Earlytreated and Chronic-treated persons Namazi, et al. JID 2018 18 Namazi, et al. JID 2018 Durability of Virologic Control Conclusions Proportion suppressed at: Year 1: 75% Year 2: 55% Year 3: 41% Year 4: 30% Year 5: 22% 2 PTC treated during early infection maintained durable suppression > 10 years 13% of early-treated and 4% of chronic-treated participants met PTC definition Persons treated during early HIV may have lower barrier HIV remission PTCs relatively stable CD4 during 24 weeks post TI - Durability and magnitude of associated systemic inflammation unknown Many HIV cure study designs involve short analytical treatment interruption (TI) with RT restarted at some rebound VL threshold. With weekly VL monitoring: - TI trials that restart RT at VL 1000 copy threshold will miss 50% of PTC - TI trials that restart RT at VL 10,000 copy threshold will miss 33% of PTC Namazi, et al. JID 2018 20 Namazi, et al. JID 2018
21 23 24 22 Rapid RT how early is early enough? Post-treatment control is it real? Using molecular epidemiology to interrupt transmissions during recent infection Sexual Transmission During Recent Infection 1) Montreal: Phylogenetic analysis of transmission chains: Estimated early infection accounted for 49.4% of transmissions 1 2) Uganda: Estimated the probability of transmission 49% (27-70) during primary infection (duration 2.90 mo [1.23-6.00]) 2 3) Malawi: Estimated that early infection gave rise to 38.4% (95% credible interval 18.6-52.3) of transmissions 3 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 diversity 4 5) Swiss cohort: Estimated 43.7% (range 41-56%) of transmissions occurred during the first year of infection 5 1renner G, et al. JID 2007; 2Hollingsworth TD, et al. JID 2008; 3Powers K, et al. Lancet 2011; 4Volz EM, et al. PLoS Med 2013; 5Marzel, et al. CID 2016 Molecular Epidemiology and HIV Prevention CDC PS18-1802 Document (2017) - Identifies transmission clusters for investigation and intervention Priority: Clusters most concerning for recent, rapid transmission and growth that could represent an outbreak. Clustering at a low genetic threshold (0.5%) consistent with recent transmission 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 What is an HIV Transmission Network? Each strain of HIV is unique Thus, each person s HIV sequence has a fingerprint-like quality. HIV-infected people can be identified as having viruses that are very similar or dissimilar. This information can be used to estimate the location, direction, rate of spread of HIV within a community. If dates of infection are known, transmission direction can be inferred. https://www.cdc.gov/hiv/pdf/funding/announcements/ps18-1802/cdc-hiv-ps18-1802-ttachmente-detecting- Investigating-and-Responding-to-HIV-Transmission-Clusters.pdf
25 28 26 Defining a Cluster: Using Pairwise Genetic Distance Clustered = elow genetic distance threshold Newly HIV Diagnosed GD<0.02 NT subt/site Wertheim, et al. PLoS Pathog. 2017 Wertheim, et al. PLoS Pathog. 2017 Epidemiologic Linkage etween Two Hosts Public Health Intervention to HIV Hotspots Epidemiologic Linkage U1 U1 U1 U 2 Genetic Linkage Near real-time phylogenetic monitoring of HIV in ritish Columbia New sequences trigger an automated reanalysis of entire database In June 2014, a rapidly expanding cluster was noted - 11 new cases/3 months - including 8 with NNRTI TDR Enhanced public health follow-up implemented 27 dapted from Romero-Severson et al. PNS 2016 Poon FY, et al. Lancet HIV. 2016
29 31 30 Timeline of Cluster 55 Outbreak Limitations New Diagnosis Drug resistance No resistance 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 Data sharing has many benefits, but also some risks Poon FY, et al. Lancet HIV. 2016 Conclusions HI likely a significant driver of HIV transmission Same day RT for cute/early HIV will rapidly reduce transmission risk and maximize immunologic outcomes Persons treated during early HIV may have lower barrier to achieving HIV remission TIs 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 Questions?