Cure: Early Detection and Early Treatment"

Transcription

1 Cure: Early Detection and Early Treatment" ECHO (RV217) and RV 254 Merlin L. Robb, MD, Dr. Jintanat Ananworanich, and Dr. Jerome Kim and Dr. Nelson Michael 4 th International Workshop on HIV & Women January 2014 Washington, DC The views expressed are those of the presenter and should not be construed to represent the positions of the U.S. Army or DoD

2 MHRP Acute Infection and Cure Review status of Acute HIV Infection studies RV 217 Viral dynamics and set-point Symptoms and signs RV 254 Measures of reservoir at entry and over time after HAART or megahaart Review Cure Intervention Study Plans

3 RV 217: ECHO Methods Recruit locations with transactional sex MSM & TG in Thailand Females in Africa Enroll 2000 using ACASI: Exchange goods for sex Unprotected sex w/ HIV+ Unprotected sex w/ >3 partner reported STI symptom

4 Phase I: surveillance RV217 Study Design Twice weekly finger stick (600 µl) x 12 months then monthly x 12 months qualitative HIV RNA in real time (APTIMA) LOD: 28 cps/ml (50%); 50 cps/ml (80%) Phase IB: enter if APTIMA reactive Bi-weekly blood collections (30-90 ml) Confirms diagnosis and enters phase II or, Establishes false positive result and returns to phase I Phase II is HIV infection follow-up for up to 5 years

5 Incident case Retention and Visit Compliance Overall HIV prevalence = 29.4% Incidence: 2.45% to 6% Entered stutter phase: 239 Confirmed HIV infected: 95 (39.7%) Lost to follow-up = 6 1/13/2014

6 Differences by Region Virtually all biologic males in Thailand versus all female in East Africa Different HLA Different route of transmission Different endemic diseases and states of immune activation Different HIV subtypes

7 Aggregate Priority 1 Viral Loads- 1 st 100 days (n=42) Median interval: last negative to first positive = 4 days (range 2-32) Nadir VL Min VL Prior to Day 60 Set-Point Average VL Day 80 and Day 360 minimum two measurements Upslope Day 0 = Last Negative if Last Negative < 10 days prior to VL Day 0 = 1 st pos RNA Blood collections

8 Regional differences in Viral Load

9 Viral Load by region (days) VL > in males: Reported in US populations: NEJM (2001): 344 (10): p720 Reported in Africa: JID (2004): 189: p1209 Early Nadir

10 Correlation of VL peak and upslope to set point **No correlation between VL downslope and set-pt

11 Correlation of VL nadir to set point

12 Correlation of set point VL to CD4 count outcomes

13 Soluble factor changes in AHI

14 RV 217 Conclusions Events in Acute Infection in the first 30 days after the advent of viremia dictate disease course Some evidence for pre-peak events predictive

15 During Acute Infection Window Africa (n=25) Thailand (n=17) All (n=42) Symptom: N(%) N(%) N(%) Fever 14 (56%) 7 (41%) 21 (50%) Headache 12 (48%) 6 (35%) 18 (43%) Feeling of Illness 11 (44%) 5 (29%) 16 (38%) Abnormality: Lymph* 2 (8%) 16 (94%) 18 (43%) HEENT** 3 (12%) 15 (88%) 18 (43%) Cardiovascular 12 (48%) 5 (29%) 17 (40%) *Fisher s Exact p-value < **Fisher s Exact p-value <0.001 Although fever a common complaint only 4 cases documented temperature elevation and none above 102F

16 Frequency of signs and symptoms Significant correlation between peak viral load and total number of symptoms reported in recent medical history (rho=0.3721, p=0.0153) No correlation between total number of physical exam findings and peak viral load Recent Medical History Physical Abnormalities

17 Recent Medical History Heat Map

18 Physical Abnormalities Heat Map

19 RV 217 Conclusions Events in Acute Infection in the first 30 days after the advent of viremia dictate disease course Some evidence for pre-peak events predictive If acute infection is important and we wish to intervene, it won t be easy to identify

20 RV254/SEARCH 010 Study Establish and characterize an acute HIV infection cohort in a high risk population and evaluate interventions for cure

21 Thai Red Cross Anonymous Clinic (April 2009 to 10 August 2013) 80,557 sensitive HIV EIA (Ag-Ab combo assay) 5,523 positive Less sensitive HIV EIA 75,034 negative Pooled NAT 5,443 positive 80 negative 59 positive 74,975 negative Chronic HIV 139 acute HIV HIV Not infected HIV RNA diagnosed HIV earlier than sensitive EIA by 5 days

22 SEARCH 010/RV 254 study: Acute HIV enrollment/compartment studies/new drugs Real-time screening of 80,557 samples in Bangkok by pooled nucleic acid and sequential EIA Acute HIV infection (AHI) confirmed (n= 139) 3 days 114 AHI enrolled 51% F I/II Main protocol (n=114) Optional procedures ARV protocol (n=111) 2 days - Clinical characterization - Phlebotomy - Sigmoid biopsy (n=80) - Leukapheresis (n=70) - Lumbar puncture (n=69) - MRI/MRS (n=103) - Genital secretion (n=107) - Inguinal LN biopsy (n=2) MegaHAART (n=60) HAART (n=51) Updated from Ananworanich J, PLoS ONE

23 HIV RNA between megahaart vs. HAART

24 Total HIV DNA in PBMC Integrated HIV DNA in PBMC

25 Almost all subjects treated during acute HIV had undetectable integrated HIV DNA after 1 year of ART 100% 89%

26 Clinical Trials of ART during Acute/Primary HIV Infection followed by ART Interruption Published Studies VISCONTI (n=32) ART during PHI (Hocqueloux L, AIDS 2010) Swiss HIV Cohort Study (n=32) ART during acute vs. Chronic HIV (Gianella S, Antiviral Therapy 2011) Primo-SHM (n=173) No ART vs. 24 weeks vs. 60 weeks ART (Grijsen ML, PLoS Medicine 2012) ANRS CO6 PRIMO (n=164) ART during PHI (Goujard C, Antiviral Ther 2012) CASCADE (n=259) ART during PHI (Lodi S, Arch Intern Med 2012) Viremic control 15.6% had VL < 50 for > 6 years 3 of 32 (9%) had VL < 50 at 1 year 4 of 79 (5%) in ART arms had VL < 100 at wk 24 VL < 50 11% at 1 year, 8.5% at 2 years VL < % at 1 year and 5.5% at 2 years

27 Cure Strategies to Evaluate in RV 254 Objective 1 Is early ART alone sufficient to cure in patients treated during Fiebig I? Objective 2 Will therapeutic HIV vaccine + early ART result in better viremic control vs. early ART alone? Where we are now in RV254/ SEARCH 010 ART initiated during acute HIV restricted infection in PBMCs and T CM A series of randomized trials are being developed Goal Functional cure (Viremic control without ART) Objective 3 Will HDACi + early ART result in depletion of reservoir/cure vs. early ART alone? Objective 4 Will anti-inflammatory drugs or broadly neutralizing mab + early ART = less activation and reservoir vs. early ART alone?

28 Objective 1: Is early ART alone sufficient to cure in patients treated during Fiebig I? 11 patients Initiated ART during Fiebig I and viral suppression for 2 years with no viral blip for the past 1 year Step-wise interruption Step 1: 6 subjects If at least 1 out of 6 is a success (viremia < 100 copies/ml at week 24), go to step 2 Step 2: 5 subjects ART resumption criteria VL > 1000 copies/ml or a rapid rise in VL Persistent low level viremia above 100 copies/ml

29 VRC mab 01 administered during acute infection Shingai et al mab reduced SHIV viremia to undetectable in 3 days Barouch et al mab reduced SHIV viremia 3 logs in 7 days

30 VRC mab 01 administered during acute infection Enrollment among RV 217 participants 1) Aptima reactive at SBV and visit 1 of phase IB 2) WB negative, ie FI to FIII Interventions 1) Study agent VRC-HIVVRC AB (VRC01) monoclonal antibody, 40 mg/kg IV 2) ART: TDF/FTC/EFV in daily fixed dose combination

31 VRC mab 01 administered during acute infection Design Participants enter after second reactive Aptima (or VL) Group 1 (n = 7) ART alone in AHI on day 0 Group 2 (n= 7) ART with single infusion of 40 mg/kg VRC01 on day 0 Group 3 (n= 7) single infusion of 40 mg/kg VRC01 on day 0 followed by ART initiation on day 7 All groups will subsequently be followed for 24 weeks. ATI depending on reservoir measures in those who remain suppressed?

32 VRC mab 01 administered during acute infection

33 RV 217 Summary 1) Enrollment continues per current amendment 2) AHI cases in Thailand are offered enrollment in RV 254 3) Increasing CD4 threshold for HAART to 500 will permit most AHI cases to go on treatment 4) We will propose to amend RV 217 to a) continue enrollment to acquire 21 more cases for VRC01 mab or b) enter HAART/megaHAART suppression similar to RV254

34 Conclusions Events in acute infection are determinants of long term outcome Reservoir evolves quantitatively and qualitatively during AHI and early infection and may be more amenable to intervention Evaluating interventions in small, exploratory trials in this setting may provide more rapid down-selection of effective approaches and define the reservoir and biomarkers predicting functional cure Capturing these populations in acute infection requires special cohort studies depending upon the goals of the intervention

35 A special thanks to all RV217 and RV 254 volunteers! MHRP-Rockville Nelson Michael Jerome Kim Leigh Anne Eller Sheila Peel Linda Jagodzinski Jennifer Malia Mary Marovich Michael Eller Bonnie Slike Gustavo Kijak Sodsai Tovanabutra Eric Sanders-Buell Morgane Rolland Aimee Bolen Mark Milazzo Amy Weintrob AFRIMS-Thailand Sorachai Nitayaphan Somchai Sriplienchan Eugene Kroon Viseth Ngauy Mark de Souza Susan Mason MUWRP-Uganda Arthur Sekiziyivu Hannah Kibuuka P Lillian Mutengu Ali Taylor Britta Flach Oxford Nilu Goonetilleke DAIDS Edith Swann Phil Renzullo MMRP-Tanzania Lucas Maganga Leonard Maboko Phillip Mann Erica Sanga Michael Hoelscher Cornelia Lueer Thai Red Cross/Chula Jintanat Ananworanich Praphan Phanuphak Nittaya Phanuphak Frits van Griensven Thep Chalermchai James Fletcher Eugene Kroon Nipat Teeratakulpisarn Rungsun Rerknimitr WRP-Kericho Kathleen Rono Doug Shaffer Fred Sawe Kibet Shikuku Samoel Khamadi