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Acute HIV infection

Acute HIV infection. Christian B. Ramers, MD Duke Medicine-Pediatrics Residency Program. Overview. Definition Epidemiology Clinical Features Lab Diagnosis/Virological Characteristics Treatment options Tanzania’s policies Cases. What is Acute Anti-retroviral Syndrome?.

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Acute HIV infection

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  1. Acute HIV infection Christian B. Ramers, MD Duke Medicine-Pediatrics Residency Program

  2. Overview • Definition • Epidemiology • Clinical Features • Lab Diagnosis/Virological Characteristics • Treatment options • Tanzania’s policies • Cases

  3. What is Acute Anti-retroviral Syndrome? • Earliest stage if HIV infection usually occurring days to weeks after exposure, but encompasses any infection recognized prior to seroconversion • Characterized by: • Flu-like or ‘Mono-like’ illness • HIV RNA >100,000 copies/mL • Widespread dissemination of HIV in lymphoid tissues • Negative HIV Antibody by ELISA • Extremely high infectivity • Median time to seroconversion is 25 days, but can be as long as 6 months

  4. Presenting Signs/Symptoms • Roughly 75% (50-90%) will have symptoms • Usually appear days to weeks after exposure • Fever (80-90%), fatigue (70-90%), anorexia (30-60%) • Rash (40-80%)– often erythematous maculopapular • Pharyngitis (50-70%) • Generalized lymphadenopathy (40-70%) • Mucocutaneous Ulceration (oral 10-20%, genital 5-15%) • Headache (32-70%), often retroorbital with meningismus • Neurologic: Aseptic meningitis (24%), radiculitis, myelitis • May present with OI, thrush, zoster (if CD4 depressed) * Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

  5. Pathophysiology • Langerhans cells (submucosal dendritic cells) are first to be infected via CD4 and CCR5 receptors • Dendritic cells then cluster at local lymph nodes and pass on virus preferentially to memory • Animal models show HIV in internal iliac LN’s by day 2 • Viremia develops within 4-11 days and proceeds uncontrolled reaching >100,000 copies/mL • Initial antibody responses are weak and control of viremia is mostly by potent CD8 cytotoxic cells • Viral ‘set point’ reached by 6 months with significant prognostic value From www.HIV Webstudy.com – University of Washington 2006

  6. Acute HIV syndrome Data from Vanhems et al 2000, showing clinical features of 160 pts with acute HIV infection compiled from Geneva, Seattle, and Sydney Establishment of viral ‘set point’. Modified from Walker BD, Goulder PJ. AIDS. Escape from the immune system. Nature. 2000;407:313-4.

  7. Laboratory Evaluation • Must send plasma HIV RNA RT-PCR as well as ELISA to confirm diagnosis. • RNA-PCR available at KCMC for TSh 5,000 • RT-PCR positive within 11 days of infection • Any positive Ab or RT-PCR should be immediately confirmed to avoid conveying false positive results • Viral load typically very high (>100,000 copies/mL) • Many associated Lab abnormalities: • Anemia, Leukopenia (40%), Thrombocytopenia (45%) • Transaminitis (21%), CSF pleiocytosis (24%) • Hyponatremia?, high total protein? * Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

  8. Laboratory Evaluation - continued *United Republic of Tanzania – Ministry of Health. National AIDS Control Programme. National Guidelines for the Clinical Management of HIV and AIDS. Second Edition, April 2005

  9. Laboratory Evaluation - continued • Baseline lab evaluation is typically sent at initial outpatient HIV clinic visit: • Confirmatory RT-PCR and ELISA if not done • Viral Genotyping is recommended • (up to 15-20% of acute HIV caused by resistant strains) • Baseline CBC, Chem 7, GI Panel, Lipids • PPD, Hepatitis Serologies, Toxo IgG • CXR, EKG, Pap smear * Hammer SM. Clinical Practice: Management of Newly Diagnosed HIV Infection. NEJM 2005; 353 (16): 1702-10

  10. Malaria Primary CMV Drug reaction Infectious Mononucleosis (EBV) Viral Hepatitis (A, B, C) Primary HSV Influenza Trypanosomiasis Parainfluenza RSV Severe GAS pharyngitis Secondary Syphilis Toxoplasmosis Rubella Rickettsial diseases Index of Suspicion is Key!! Differential Diagnosis Includes:

  11. Initial Counseling • Patients need extensive support during initial infection, especially to allow acceptance • Safe sex pracitices must be reinforced since patients are most infectious during acute infection • Emphasis should be placed on HIV being chronic infection which should not be life-limiting • Initiation of ART is a highly individualized decision between HIV provider and patient taking in to account social support, patient readiness, current recommendations on viral load/CD4 parameters

  12. Clinical Course • Patients are typically symptomatic for 14 days, but lymphadenopathy and some laboratory abnormalities may persist longer • In absence of ART viral load decreases in 8-12weeks to ‘set point’ usually 1-10,000 copies/mL • Diagnosis may be missed in 75% of cases • Asymptomatic latent phase of infection ensues over next 5-10 years with gradual depletion of CD4/CD8 cells with destruction of lymph node architecture * Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

  13. Duration of Latent Period – WHO stage I • Cohort studies from Haiti and Kenya suggest a 4 to 7 yr asymptomatic latent period prior to clinical AIDS (shorter than in US – 8-10 yrs) • Acceleration of immuno-suppression in Africa thought to be due to activation of HIV-infected immune cells by Tuberculosis, helminthitic or parasitic infections

  14. Typical course of human immunodeficiency virus (HIV) infection Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663

  15. To treat or not to treat? • Rosenberg and co-workers* have demonstrated that treating primary HIV-1 infection allows for the maintenance of T-Helper cell responses to HIV-1-specific antigens, whereas these responses are more difficult to demonstrate in similarly treated, chronically infected persons. Given the knowledge that a small, slowly decaying latent infectious reservoir is established very early in the course of HIV-1 infection, the maintenance of these immune responses may be critical if the ultimate goal of immune control of HIV-1 is to be achieved. * Rosenberg E, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997;278:1447-50

  16. Advantages and Disadvantages • Advantages: • Decrease in duration/severity of primary illness • May lower initial viral load set point • Slows disease progression • Enhances recovery of CD4 cell populations • Early therapy may reduce rates of viral mutations • Decreases viral transmission • 10-20X more infectious in acute stage • 50% of transmission due to acute hyperinfectiousness • Disadvantages: • Side effects may adversely affect quality of life • Establishing adherence may be difficult in acute illness • More ARV exposure  more ARV resistance From HIV Webstudy – University of Washington 2006

  17. Who gets ARV’s in Tanzania? • d4T/3TC/NVP (triomune) • AZT/3TC/NVP • d4T/3TC/EFV (if Tb/anemia) • AZT/3TC/EFV (if Tb) • AZT/ddI/Lop-r • ABC/ddI/Lop-r *United Republic of Tanzania – Ministry of Health. National AIDS Control Programme. National Guidelines for the Clinical Management of HIV and AIDS. Second Edition, April 2005

  18. Revised WHO clinical staging of HIV

  19. Revised WHO clinical staging of HIV

  20. Long-term Non-Progressors (LTNP’s) • Only compose 5% of HIV infected pts • Characterized by absence of progression from HIV infection to AIDS even in the absence of ART for > 10 years • Have been observed to have more preserved anti-HIV CD-4 proliferative responses and higher CD-8 Cytotoxic responses Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663 Pantaleo G, et al. N Eng J Med 1995;332: 209-16; Cao Y, et al. N EngI J Med 1994:332:201-8; Haynes B, et al. Science 1996;271:324-7.

  21. HAART in 2007 Atripla – approved July 2006: fixed-dose combination of Efavirenz, Emtricitabine, Tenofovir; i tab PO QD 2006 – >25 antiretrovirals available

  22. Recommended ART Regimens in Tanzania

  23. Initial Dx (9/6/06) CD4+ = 66 VL = > 750,000 copies/mL ID clinic (9/20/06) CD4+ = 188 VL = < 100 copies/mL Reason for Optimism

  24. Case Presentation#1 A 27 yo previously healthy man presents to casualty complaining of 2 d of fever, sore throat, and generalized body malaise and you note cervical and axillary LAD, mild meningismus and a diffuse maculopapular rash on PEX. On further history, he notes an episode of unprotected intercourse roughly 3 wks prior. Acute HIV infection is suspected. Which of the following is true regarding acute HIV? • < 5% of acute HIV results in clinical illness • >80% of symptomatic acute HIV presents with aseptic meningitis. • Patients recently infected with HIV typically have viral loads in excess of 50,000 copies/mL within 4 weeks of infection • A negative HIV antibody and a viral load of 2,000 copies/mL is consistent with acute HIV infection

  25. Case Presentation#1 A 27 yo previously healthy man presents to casualty complaining of 2 d of fever, sore throat, and generalized body malaise and you note cervical and axillary LAD, mild meningismus and a diffuse maculopapular rash on PEX. On further history, he notes an episode of unprotected intercourse roughly 3 wks prior. Acute HIV infection is suspected. Which of the following is true regarding acute HIV? • < 5% of acute HIV results in clinical illness • >80% of symptomatic acute HIV presents with aseptic meningitis. • Patients recently infected with HIV typically have viral loads in excess of 50,000 copies/mL within 4 weeks of infection • A negative HIV antibody and a viral load of 2,000 copies/mL is consistent with acute HIV infection

  26. Acute HIV syndrome • Viremia detectable by RT-PCR within 4-11 days • Roughly 40-90% of acute infections have symptomatic phase lasting 1-2 wks within 28 days of initial exposure • High Viral Loads (>100K) are reached within 2-3 weeks but fall by 6 months to a ‘set point’ largely determined by strength of CD8 cytotoxic T-cell response, which may predict progression • Dx only by RT-PCR as sero-conversion takes 1-3 mos • Pts are HIGHLY infectious in acute phase making early dx and counseling essential to prevent spread • Initiating therapy during this period is controversial with no established standard of care

  27. References • CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm, Additional Resources: http://www.hivatis.org , http://www.hivinsite.org , http://www.aidsinfo.nih.gov • Merson, MH. The HIV-AIDS Pandemic at 25—The Global Response. NEJM, 2006; 354: 2414-2417 • Hammer SM. Management of Newly Diagnosed HIV Infection. NEJM 2005; 353:1702-10 • Kim JY and Farmer P. AIDS in 2006 – Moving Toward One World, One hope? NEJM 2006; 355(7): 645-7 • UNAIDS – 2006 report on the Global AIDS epidemic • Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39 • Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663 • Rosenberg E. et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997;278:1447-50 • Pantaleo G, et al. N Eng J Med 1995;332: 209-16 • Cao Y, et al. N EngI J Med 1994:332:201-8 • Haynes B, et al. Science 1996;271:324-7.

  28. Clinical & Educational Resources • UW Case-based HIV learning site: http://depts.washington.edu/hivaids/ • CDC PEP guidelines: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm • Hopkins HIV guide: http://www.hopkins-hivguide.org/ • MGH/BWH image database: http://www.idimages.org/ • Baylor Pediatric AIDS Initiative: http://bayloraids.org/ • Hopkins online lectures ‘Principles of Anti-Retroviral Therapies’: http://www.ccghe.jhmi.edu/CCG/distance/HIV_Courses/art.asp#Principles • IDSA/HIVMA practice guidelines: http://www.idsociety.org/HIVMA_Template.cfm?Section=Practice_Guidelines2 • CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm , http://www.cdc.gov/hiv/topics/surveillance/resources/slides/index.htm • Additional Resources: http://www.hivatis.org • Additional Resources: http://www.hivinsite.org • Additional Resources: http://www.aidsinfo.nih.gov

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