Acute HIV Infection Translating Pathogenesis into Opportunity Eric S. Rosenberg, M.D. Associate Professor of Medicine Massachusetts General Hospital Harvard Medical School [email protected].
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Acute HIV Infection Translating Pathogenesis into Opportunity Eric S. Rosenberg, M.D. Associate Professor of Medicine Massachusetts General Hospital Harvard Medical School [email protected] 47 year old male • Present to MGH ED with an 8 day history of : Fever to 102.5 Headache Photophobia Myalgias and arthralgias Nausea and vomiting 3rd visit to health care system 47 year old male Additional history: Recent unprotected sex with an HIV infected partner PMH: prior history of syphilis Exam: Fever Cervical lymphadenopathy Rash (started on torso spread to limbs and scalp) 47 year old male Diagnostics: Test for EBV, CMV, influenza were negative HIV ELISA Negative Western Blot negative (no bands) HIV RNA > 750,000 copies/ml 1:100 dilution 47,000,000 copies/ml CD4 count = 432 cells Diagnosis Acute HIV infection Framing the Question MGH-NCSU collaboration Should this individual be treated with antiretroviral therapy?? Acute HIV infection Goals 1. To discuss the advantages and disadvantages of treating individuals with acute HIV 2. To review the early biological events of acute HIV infection 3. To review the immunologic rationale for treatment during acute infection and possible treatment interruption Should individuals with Acute HIV-1 infection be treated with antiretroviral therapy? Advantages Preservation of HIV-specific cellular immune responses Opportunity for structured treatment interruption Lowering of HIV-1 set point Limitation of viral evolution and diversity Decreased transmission Mitigation of acute retroviral symptoms Disadvantages Toxicities and unknown longterm risks Short- and long-term clinical benefits are not well-defined Resistance acquisition Limitation of future antiretroviral therapy options Quality of life impact Cost Kassutto et al, CID 2006 Understanding the terminology and variables that can be measured Viral Load = Speed of the train CD4 count = Distance from cliff Antiviral therapy/host immune response = Brakes HIV infection J. Coffin, XI International Conf. on AIDS, Vancouver, 1996 The Dynamics of Acute HIV Infection HIV Viral Load Interquartile ranges Rapid Progression 59, 987 HIV Ab Slow Progression 2-8 weeks 6-12 months 28, 240 11,843 Lyles et al, 2000 Since the level of HIV in the blood predicts progression, What factors influence viral replication? Viral factors Host genetic factors Host immune responses Humoral immune response Neutralizing Antibodies New virus assembly B cell Why do neutralizing antibodies fail? • Viral debris • Rapid evolution and diversification of HIV (horse is already out of the barn) • Inadequate T cell “help” Cellular Immune Responses New virus assembly 2-3 Days Soluble factors If CTL are present, why is the immune response not more effective in HIV infection? HIV-Specific T Helper Cells are impaired in all stages of disease Class II 1. Activation 2. Clonal expansion TCR CD4 Antigen Presenting Cell CD4+ Th Cell 3. Cytokine secretion Critical relationship between CD4 and CD8 Opportunity #1 Rescue of HIV-specific T helper cells Hypothesis (pathogenesis): • HIV-specific T helper cell (CD4) responses are impaired during acute infection Hypothesis (opportunity): • Treatment with ARV during acute infection will protect these responses from being lost CD4 cells Activation & Expansion Class II TCR CD4 Infection Impairment CD4 cells Activation & Expansion Class II TCR CD4 Antiretroviral therapy Characteristic Median age (years) [IQR] Male gender (%) HIV Risk Factor MSM (%) White race (%) Mean baseline VL (copies/mL) (range) Mean baseline CD4 (cells/mm3) (range) Acute Early total n 35 [31,39] 37 [34,43] 102 94 94 102 82 81 94 77 78 102 382,000 (2800-2.95 million) 75 567 (170-981) 100 5.61 million (11,000-95 million) 445 (42-1093) Kassutto et al, CID 2006 Spontaneously control virus Stimulation index 1000 100 10 1 control chronic acute No Rx acute LTNP Rx Rosenberg et al, Science 1997 Observation • Immune damage occurs in the earliest stages of acute HIV infection, but there appears to be a “window of opportunity” to reverse this damage with treatment Opportunity #2 Can treatment be initiated during acute HIV infection and then discontinued? Lessons from Berlin Lisziewicz et al, NEJM 340 (21), 1999 Augment HIV-specific immunity STI Hypothesis RX RX RX CTL Magnitude RX Th Viral Load Time Can therapy be discontinued? • Will HIV-1-specific immune responses generated and maintained during acute infection be enough to control viremia? • If virus returns once therapy is discontinued, can this “snap-shot” of autologous virus further boost the immune system? Structured treatment interruption • Several patterns have emerged • Failure • Transient control of viremia with sudden loss of containment • Control (durability?) Rosenberg et al, Nature 2000 Kaufmann et al, PLoS Med 2004 Opportunity #3 There is more translating to do… Each patient tells a different story 200000 VIral load AC-02 150000 STI cycle #1 100000 50000 0 0 5 10 15 20 Days off therapy 25 30 200000 Viral load AC-02 150000 STI cycle #2 100000 50000 0 0 500 1000 1500 Days off therapy 2000 AC-10 50000 Viral load 40000 30000 20000 10000 0 0 500 1000 1500 Days off therapy 2000 AC-10 (1.5 years on therapy) HIV-1 RNA Autol Nab 100 10 1 0 50 Montefiori, J Virology 2001 6000 5000 4000 3000 2000 1000 0 100 150 200 250 Days off therapy Plasma HIV-1 RNA Neutralizing antibody titer 1000 5g 5a 6c 3a 5e 6m 2f What is unique about treated acute infection? Lack of viral diversification 99 2e 6d 2b 2i 1m 1j 1i 6g 96 6j 6k 1a 3f 5m 2c 3c 1n 5f 6n 1e 2d 5i 5n 99 2a 1d 2j 5l 6b Chronic pt. 10 3d 3g 6f 6e 4b 1c 1f 1g 5o 5j 100 100 Jrfl NL43 Hxb2 2h 2k 6l 5d 1b 3b 3h 4a 5k 2g 1h 1k 1l 6i 5c 3e 5b 5h 97 6h 77 100 1b 2b 1a 1c 2c 1d 1a 1b 1c 1d 1e 1f 1g 2a 2b 2c 2d 2h 89-6 2f Acute pt. Acute pt. AC-06 150000 8.8 x 106 100000 50000 < 50 12 months 24 months 36 months 48 months Cellular Immune Responses New virus assembly 2-3 Days Soluble factors 31 45 VRHFPRIWLHGLGQH 243 226 WRKLVDFRELNKRTQDFW 242 259 FWEVQLGIPHPAGLKKK 295 309 NCTRPNNNTRKSIHI 766 780 FSYRRLRDLLLIAAR 842 856 HIPRRIRQGLERALL 308 322 WKGSPAIFQSSMTKI 423 437 SQIYPGIKVRQLCKL 521 504 LKTGKYARMRGAHTNDVK 894 911 AVFIHNFKRKGGIGGYSA gag 793 1 631 pol 2088 2295 TACQGVGGPGHKAPVL 363 348 HPVHAGPIAPGQMREPR 216 232 GATPQDLNTMLNTV 178 191 SPRTLNAWVKVVEEK 148 162 WEKIRLRPGGKKKYK 16 30 65 79 EVGFPVTPQVLRPM 75 89 PLRPMTYKAAVDLSH vpr vif 5562 5853vpu 5044 5622 6070 6302 5099 nef env 6230 5834 6048 5973 6048 8807 9431 8805 tat rev 8368 8458 8368 8663 ERILSTYLGRSAEPV 57 71 KKTKPPLPSVKKLT 170 157 THPRVSSEVHIPLG 47 60 KSLVKHHMYISKKAK 22 36 QVDRMRIRTWKSLVK 26 12 RRQDILDLWIYHTQG 119 105 TYKSSVDLSHFLKEK 80 94 VTPQVPLRPMTYKAA 70 84 AC-06 150000 8.8 x 106 100000 50000 < 50 12 months 24 months 36 months 48 months AC-06 150000 8.8 x 106 100000 50000 < 50 12 months 24 months 36 months 48 months Viral peptide in HLA Binding Groove V S N Y T T A L L HLA Class I molecule Immune escape in anchor residues F S V N Y T A T HLA Class I molecule L Viral Variation in Gag KIRLRPGGK-A03 RLRPGGKKKY-A03 Day 18 MGARASVLSGGELDKWEKIRLRPGGKKKYRLKHIVWASRELERFALNPSLLETSGGCRQILGQLQPSLQTGSEELKSLFNTIAVLYCVHQRIDVKDTKEA> Day 1170 ..........................T.K...............V..G............K..H.............Y..V.T........EIR.....> SPRTLNAWV-B07 TPQDLNTML-B07 Day 18 LDKIEEEQNKTKKKAQQAAADTGNSSQVSQNYPIVQNLQGQMVHQPISPRTLNAWVKVVEEKAFSPEVIPMFTALSEGATPQDLNTMLNTVGGHQAAMQM> Day 1170 .........C..RE..............................S..........................S...........................> HPVHAGPIA-B07 Day 18 LKETINEEAAEWDRLHPVHAGPIAPGQMREPRGSDIAGTTSTLQEQIAWMTNNPPIPVGDIYKRWIILGLNKIVRMYSPSSILDIKQGPKEPFRDYVDRF> Day 1170 .............M.......V........................Q...S...V...E...................T....................> GPGHKARVL-B07 Day 18 YKTLRAEQASQDVKNWMTETLLVQNSNPDCKTILKALGPAATLEEMMTACQGVGGPGHKARVLAEAMSQMTSPANIMMQRGNFKNQRKIVKCFNCGKEGH> Day 1170 ..........E..G..........A.............G.............................V.NS.T........R....T...........> Day 18 IARNCRAPRKKGCWKCGQEGHQMKDCTERQANFLGKIWPSHKGRPGNFLQSRPEPTAPPAESLMFGEETTTPPQKQEPRDKELYPPLASLRSLFGNDPSSQ> Day1170...........................................................E..VR.....A..S...GTI......-...............> Altfeld et al , Nature Presence of Two Distinct Viruses Altfeld et al , Nature Is the “possibility” of STI enough reason to treat individuals during acute HIV infection? Enough question exists regarding the use of STI as a management strategy that the most relevant question in 2008 is whether or not to treat during acute infection Conclusions • It is not known whether treatment during acute infection is the correct thing to do • STI may have a role in management of individuals treated during acute infection but optimal approach not known. • Mathematical and statistical modeling (NCSUMGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.