* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download HIV Pathogenesis 2000: Clinical implications
Survey
Document related concepts
Cancer immunotherapy wikipedia , lookup
Common cold wikipedia , lookup
Urinary tract infection wikipedia , lookup
Adaptive immune system wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Innate immune system wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Acute pancreatitis wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Hospital-acquired infection wikipedia , lookup
Hepatitis C wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Neonatal infection wikipedia , lookup
Infection control wikipedia , lookup
Transcript
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: MSM Recent unprotected sex with an HIV infected partner PMH: prior hx 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 Positive 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 = 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 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 What happens to HIV-specific T helper cells? The acute infection hypothesis 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 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 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. • Robust mathematical and statistical modeling (NCSU-MGH) to inform the design of the first randomized trial of treatment versus no treatment during acute HIV.