Acute HIV infection: Implication for HIV Control and Cure

Transcription

1 Acute HIV infection: Implication for HIV Control and Cure Jintanat Ananworanich, MD, PhD Deputy Director in Scientific Affairs, HIV-NAT Chief, SEARCH The Thai Red Cross AIDS Research Centre Bangkok, Thailand ; Jintanat.A@hivnat.org

2 Outline Importance of intervening during acute HIV infection in HIV control and cure Diagnosis of acute HIV infection and clinical management Treatment during acute HIV infection SEARCH 010/RV 254 study Implication on HIV control Implication on HIV cure Functional cure (Viremic control following ART interruption) HIV cure in the pediatric population

3 Acute HIV Infection Research: Implication for HIV Control and Cure Identification of subjects during acute HIV infection (first 4 weeks of infection) Diagnose HIV at height of transmission potential Control HIV Spread Intervene to preserve Immunity, limit viral replication and reservoir Understand early immunologic and virologic events Design preventive vaccine and treatment strategies Achieve functional cure (Undetectable plasma HIV RNA without ART)

4 Fiebig Laboratory Staging of Acute HIV Infection Acute < 4 wk Early 4 wk- 6 mo Chronic > 6 mo Fiebig I (1-2 wk) Fiebig II (2-3 wks) Fiebig III/IV (3-4 wks) Fiebig EW, AIDS 2003

5 How do we know someone has acute HIV infection? Sensitive HIV EIA (Ag-Ab combo assay) Positive HIV-infected Negative Not infected Could this be acute HIV infection?

6 How do we know someone has acute HIV infection? Sensitive HIV EIA (Ag-Ab combo assay) Positive HIV-infected Less sensitive HIV EIA Negative Not infected Nucleic acid testing Positive Negative Positive Negative Chronic HIV Acute HIV Infection Not infected

7 Results from the Thai Red Cross Anonymous Clinic (April 2009 to December 2012) 58,908 sensitive HIV EIA (Ag-Ab combo assay) 4,247 positive Less sensitive HIV EIA 54,661 negative Pooled Nucleic acid testing 4190 positive 57 negative 47 positive 54,614 negative Chronic HIV 104 acute HIV Not infected Nucleic acid testing diagnosed HIV earlier than sensitive EIA by 5 days SEARCH010/RV254 study

8 Log 10 RNA copies/ml Natural History of Acute HIV Infection in Thais Median Time to VL peak= 14 days (range 7-18 days) Median VL at peak = 6.7 log (range log) Median Time to 3 rd gen EIA+ = 15 days (range 10-22) ARS symptoms days n=17 Day 0 = 1st reactive RNA RV217 study; PI: Dr. Merlin Robb (MHRP)

9 Acute Retroviral Syndrome (ARS) Symptoms % Overall 87 Fever 77 Myalgia/headache 60 Fatigue 57 Oral ulcer 53 Skin rash 50 Sore throat 50 Diarrhea 37 Adenopathy 13 Average time from onset of HIV to ARS symptoms = 11 days Almost all sought care elsewhere but none was offered HIV testing Ananworanich J, Plos One 2012

10 Should Acutely HIV-infected Patients be Started on ART? US guideline Consider ART for acute infection or seroconversion within the past 6 months WHO guideline No specific recommendation for acute/primary infection CD4 < 500 cells/mm 3 CD4 < 350 cells/mm 3 SEARCH 010 study 62 of 86 (72%) 35 of 86 (40%)

11 Antiretroviral Therapy in Acute HIV Infection PRO Decrease severity of acute retroviral syndrome Preserve immunity Reduce HIV RNA and alter viral set point Reduce risk for transmission CON Unknown long-term clinical benefit Drug toxicity Resistance Quality of life

12 25-50% of newly infected cases are from contact with early HIV-infected persons 100% ART coverage is required to eliminate HIV spread If chronic HIV infection alone is treated ART coverage for both early and chronic HIV is required to eliminate HIV spread Powers KA, Lancet 2011 No intervention % chronic +25% early +50% early Powers KA, Lancet 2011

13 SEARCH 010/RV 254 study: Acute HIV enrollment/compartment studies/new drugs Real-time screening of 58,908 samples in Bangkok by pooled nucleic acid and sequential EIA Acute HIV infection (AHI) confirmed (n= 104) 3 days Main protocol (n=86) 86 AHI enrolled Optional procedures 45% F I/II ARV protocol (n=84) 2 days - Clinical characterization - Phlebotomy - Sigmoid biopsy (n=63) - Leukapheresis (n=55) - Lumbar puncture (n=59) - MRI/MRS (n=80) - Genital secretion (n=82) MegaHAART HAART Updated from Ananworanich J, PLoS ONE

14 Characteristics Median age Values 28 years MSM 91% Median duration of infection Fiebig I Fiebig II Fiebig III 18 days 34% 11% 47% Median CD4 383 cells/mm 3 Median HIV RNA 5.6 log Bachelor degree or higher 62% Median monthly income 30,000 Baht Illicit drug use at HIV exposure 24% N of sexual partner in past month Mean 3 (max 15)

15 Reduction in Unprotected Sex after HIV Diagnosis n/n: 69/83 17/75 SEARCH 010/RV254 Study

16 Decline of HIV RNA in Semen after ART SEARCH 010/RV254 Study

17 Massive CD4 Destruction in the Gut during Acute HIV Infection HIV neg Primary HIV Brenchley JM, Douek D et al, J Exp Med 2004

18 Active depletion of CD4+ T cells in the Sigmoid during acute HIV infection in SEARCH 010 Study %CD4 1-3 wks 3-4 wks 12 months Alexandra Schuetz (AFRIMS)

19 Integrated HIV DNA in Peripheral Blood Cells is Undetectable in Fiebig I Subjects No HIV DNA in memory CD4+ subsets All undetectable Fiebig I (n=19) Fiebig III (n=25) Nicolas Chomont (VGTI-Florida)

20 Impact of Antiretroviral Therapy Instituted during Acute HIV Infection Gut CD4+ T cells immune reconstitution (Ananworanich J, PLoS ONE 2012) Polyfunctional HIV-specific CD4+ and CD8+ T cells similar to elite controllers (Cellerai C, PloS ONE 2011) Preservation and restoration of lymph node structure leading to improved survival of naïve CD4+ T cells (Zeng M, PLoS PATHOGENS 2012) Restoration of B cell function (Moir S, Blood 2010) Normalization of immune activation markers (Markowitz M, 2012 IAS HIV Cure Workshop, Abstract 16551)

21 SEARCH 010: Rapid HIV RNA Decline after ART * P < 0.05 * * HAART: TDF/FTC /EFV MegaHAART: HAART+RAL+MVC

22 Shorter Latent Reservoir Half-life when ART is Initiated during Primary HIV Infection Primary HIV Chronic HIV Half-life 5 months 44 months Time to eradicate 8 years 10 6 cells 73 years Chun TW, JID 2007; Siliciano JD, Nature Med 2003

23 Will ART Initiated during Acute HIV Infection Change the Disease Course? Viremic Control following ART Interruption

24 Trials VL < 50 after no ART French (Hocqueloux L, 2010) Swiss (Gianella S, 2011) Europe /Australia (Lodi S, 2012) Post-Treatment Controllers (PTC) Time at ART 16% 2-3 mos after diagnosis 9% 2-4 mos after infection 8% 2-3 mos after seroconversion ART duration before interruption 5 years 1.5 years 1 year PTC was associated with starting ART < 2 months from HIV exposure SEARCH 010 study: ART started < 4 weeks from history of HIV exposure

25 Early ART may Modify HIV Disease Course Elite controllers 0.5% HLA B27, B57 overrepresentation High frequencies of HIVspecific CD8+ T cells Post-ART controllers Up to 15.6% No HLA B27, B57 overrepresentation Low frequencies of HIVspecific CD8+ T cells Low HIV DNA Reservoir distribution in short-lived memory CD4+ T cells Low immune activation High CD4+ T cell count Seng R, JAIDS 2008; Hocqueloux L, AIDS 2010; McMichael AJ, Nat Rev Immunol 2010; Goujard C, Antiviral 2012, Bacchus C, 2012 IAS HIV Cure workshop

26 SEARCH 010 Total HIV DNA after ART in Early Fiebig AHI (5 yrs) Figbig I Fiebig III post-treatment controllers in ANRS PRIMO/Visconti study HIV DNA after 20 months on ART was 2.1 log HIV DNA after 6.5 years off ART was 1.71 log 1 1 Data provided by Dr. Christine Rouzioux

27 Examining interventions during acute HIV for functional cure

28 Identify acute HIV Immediate ART to minimize reservoir size preserve immunity Intervention vs. no intervention ART interruption Enrollment across multi-national sites ART New drug classes Better tissue penetration Reduce HIV replication Reduce latently Infected cells Enhance immunity Make cells resistant to HIV Control HIV viremia

29 HIV may be easier to cure in children than in adults 10 cases reported in the literature of children with positive PCR or culture with subsequent negative results High immune tolerance/low immune activation in young infants Short half life of replication competent virus from latently infected cells 11 months in early treated children vs. 44 months in adults treated during chronic infection Reports of children treated during infancy having no detectable HIV DNA, HIV-specific immunity or replication competent virus Bryson YJ, NEJM 1995; Roques PA, AIDS 1995; Persaud D, AIDS Hum Retrovirus 2007

30 HIV may be easier to cure in children than in adults 10 cases reported in the literature of children with positive PCR or culture with subsequent negative Higher immune tolerance/lower immune activation in young infants Shorter half life of replication competent virus from Could there be no HIV left latently infected cells after years of treatment? 11 months in early treated children vs. 44 months in adults treated during chronic infection Reports of children treated during infancy having no detectable HIV DNA, no HIV-specific immunity and no replication competent virus Bryson YJ, NEJM 1995; Roques PA, AIDS 1995; Persaud D, AIDS Hum Retrovirus 2007

31 Priority for testing HIV cure in children Cohort of teenagers treated with ART from early infancy and currently have no replication competent virus and no detectable HIVspecific immunity Interrupt ART Resume ART if detectable viremia Rapid transition from PMTCT prophylaxis to HAART (days after birth) Interrupt ART after 2 years of ART in children who have no replication competent virus and no detectable HIV-specific immunity

32 Conclusions Nucleic acid testing allows for identification of early Fiebig stage acute HIV infection Awareness of ARS and having low threshold for HIV testing in patients with HIV risk and ARS symptoms will enhance acute HIV detection ART during acute HIV infection is associated with preserved immunity and small reservoir size, and may alter the HIV disease course Post-treatment controllers are more common in patients treated during acute HIV infection and is associated with shorter duration from infection onset to ART initiation

33 Acknowledgements SEARCH 010/RV254 study participants and investigators Funding from the US Military HIV Research Program Antiretrovirals from the Thai Government Pharmaceutical Organization, Gilead, Merck and Pfizer Data and input for this presentation MHRP/AFRIMS Alexandra Schuetz Rapee Trichavaroj Merlin Robb Jerome Kim Nelson Michael VGTI-Florida Claire Vandergeeten Nicolas Chomont Université Paris Descartes Christine Rouzioux Thai Red Cross AIDS Research Centre Praphan Phanuphak Mark desouza Frits van Griensven Tippawan Pankam Nittaya Phanuphak James Fletcher Nitiya Chomchey Duanghathai Suttichom Peeraya Mangu Somprartthana Rattanamanee Suteeraporn Pinyakorn (Statistics)