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Primary HIV Infection

Primary HIV Infection. Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington. Primary HIV Infection (PHI) a/k/a Acute HIV Infection. Pathogenesis Clinical Presentation Diagnosis Epidemiology PHI and the Natural History of HIV Disease

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Primary HIV Infection

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  1. Primary HIV Infection Christopher Behrens, MD Northwest AIDS Education & Training Center University of Washington

  2. Primary HIV Infection (PHI)a/k/a Acute HIV Infection • Pathogenesis • Clinical Presentation • Diagnosis • Epidemiology • PHI and the Natural History of HIV Disease • Treatment Options • Conclusions & Recommendations

  3. Exposure to HIV at mucosal surface (sex) Day 0 Virus collected by dendritic cells, carried to lymph node Day 0-2 HIV replicates in CD4 cells, released into blood Day 4-11 Day 11 on Virus spreads to other organs Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

  4. Primary HIV Infection: Pathogenesis CD4 Cell Count (cells/mm³) Symptoms Plasma RNA Viral Load 1,000 CD4 Cell Count 500 4-8 Weeks Up to 12 Years 2-3 Years

  5. Epidemiology of Primary HIV Infection • United States: • 44,000 cases per year1 • 120 cases per day • Globally: 14,000 cases/day2 1. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39. 2. WHO: UNAIDS, 2001

  6. How often do people with PHI seek health care? • Swiss cohort • 87% of seroconverters (20/23) in cohort study had symptoms • 95% of these patients had medical evaluation • PHI considered in only 5 of 19 patients • PHI often leads to medical evaluation, but is under-diagnosed Schacker T et al. Ann Int Med 1996;125:257-64.

  7. Clinical Approach to the Diagnosis of Primary HIV Infection • Exposure • Signs & Symptoms • Laboratory Testing

  8. Exposure Risks (average, per episode, involving HIV-infected source patient)

  9. Primary HIV Infection: Signs & Symptoms • 40-90% of patients will be symptomatic • A mononucleosis-like illness of non-specific signs and symptoms • Signs and symptoms typically begin 1-4 weeks post-exposure • High index of suspicion is critical Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39. Schacker T, et al. Ann Intern Med. 1996;125:257-264.

  10. Primary HIV Infection: Common Signs & Symptoms N = 160 patients with PHI in Geneva, Seattle, and Sydney % of patients Vanhems P et al. AIDS 2000; 14:0375-0381. 

  11. Primary HIV Infection: Other Signs & Symptoms % of patients Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

  12. Primary HIV Infection Rash Mucosal Lesions Trunk and face > limbs Small pink macules Oral ulcers, thrush (Kahn, NEJM, 1998)

  13. Oral Ulcers in Acute HIV Infection From: Walker, B. 40th IDSA, Chicago 2002.

  14. Genital Ulcer in Acute HIV Infection From: Walker, B. 40th IDSA, Chicago 2002.

  15. Diagnostic Testing for PHI 1 mil HIV RNA 100,000 + HIV RNA HIV-1 Antibodies _ 10,000 Ab P24 + 1,000 Exposure 100 Symptoms 10 0 20 30 40 50 Days

  16. Diagnostic Testing:Viral Load • More sensitive than HIV antibody or p24 Ag test3 • Positive one to three weeks before antibody test1 • Typically high level, e.g. greater than 50,000-100,000 copies/mL2,3 • False positives can occur • Most false positives are low level (<10,000 copies/mL) • HIV VL <10,000 copies/mL should probably be considered “indeterminate” 1. Busch MP, Satten GA. Am J Med 1997;102:Suppl 5B:117-24. 2. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39. 3. Daar ES et al. Ann Intern Med. 2001;134:25-29.

  17. Diagnostic Testing: HIV Antibody • The gold standard for diagnosis of HIV infection when used with confirmatory Western Blot • Antibody conversion typically 22-27 days following infection1 1. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

  18. Why do we Care about Diagnosing PHI? • Public Health: • Patients with PHI are likely to be highly infectious • Diagnosis of HIV infection may lead to safer sex • Personal Health • 40% of patients with HIV not diagnosed until they have AIDS • Antiretroviral therapy (ART) during PHI may alter the natural course of HIV disease

  19. The Berlin Patient • Treated soon after acute HIV infection with didanosine, indinavir, and hydroxyurea • Baseline VL 80,000-89,000 pre-treatment • Treatment briefly interrupted twice in first 4 months of treatment • Viral rebound during first interruption but not the second • VL remained undetectable after treatment was stopped a third time Lisziewicz J et al. NEJM 1999; 340: 1683-1684.

  20. Unplanned Treatment Interruptions of ART following Primary HIV Infection: “the Berlin Patient” ARV Rx Started Prior to HIV Seroconversion ddI + HU + IDV No ARV Rx Lisziewicz J et al. N Engl J Med 1999;340:1683.

  21. Primary HIV Infection: Pathogenesis Anti-HIV T-cell response Sero-conversion Antibody response CD4 count(cells/mm³) Plasma RNA Viral Load Viral set point 1,000 CD4 Cell Count 500 4-8 Weeks Up to 12 Years 2-3 Years A lot of important stuff happens here

  22. From Antigen-Presenting Cell (APC) to CD4 Cell Destruction Activated CD4 Cell CD4 Cell APC HIV HIV Picture Adapted from: Cohen DE, Walker BD. Clin Infect Dis 2001;32:1756-68

  23. Loss of HIV-specific Cytotoxic T-Lymphocyte Response (CTL) CD4 Cell HIV HIV-Infected CD4 Activated CD4 Cell Lymphokines Antigen-Presenting Cells Picture Mature CD8 CTL CD8 Cell Activated CD8 Pre CTL HIV Adapted from: Cohen DE, Walker BD. Clin Infect Dis 2001;32:1756-68

  24. Cellular Immune Response to Acute HIV Infection Acute HIV Weak CTL Rapid Progression Moderate CTL Moderate Progression Strong CTL Slow Progression 6 months Slide courtesy David Spach, MD From: Walker BD. Nature 2000;407:313-4.

  25. Hypothesis Initiation of effective ART in the setting of Primary HIV Infection may preserve critical HIV-specific CD4 cells, allowing for a potentially more robust CTL response to HIV

  26. Early ART with Structured Treatment Interruptions: Theory • ART administered during primary HIV infection preserves HIV-specific CD4 cells • Allows potential for robust HIV-directed CTL response • ART interrupted periodically to ‘prime’ the immune system to recognize HIV, build CTL response • ART is re-initiated before HIV inflicts too much damage • With subsequent treatment interruptions, improved CTL response results in progressively lower viral set point • Ultimately, immune system may be able to exert adequate control over HIV without ART

  27. Structured Treatment Interruptions

  28. Structured Treatment Interruptions What’s the Evidence?

  29. STIs During PHI: Evidence From an Animal Model • ART with STIs (3 weeks on/3 weeks off) compared to standard ART in macaques acutely infected with SIV and with chronic infection • In acutely-infected macaques, viral rebound rate decreased significantly during subsequent treatment interruptions • Virologic control in these animals was associated with vigorous SIV-specific CD8-mediated immunity Lori F et al. 40th ICAAC, September 2000, abstract L-17.

  30. STIs During PHI: Evidence of Improved Virologic Control • Trial involving 14 patients diagnosed with PHI • All patients initiated combination ART during PHI, prior to seroconversion, and had full viral suppression for at least 8 months before STIs implemented • All ARVs were discontinued simultaneously • Therapy re-instituted if VL persistently (>3 weeks) over 5,000 copies/mL or if VL at any time over 50,000 copies/mL Walker B. State of the Art Lecture and Summary. 8th CROI, Session #37.

  31. STIs During PHI: Evidence of Improved Virologic Control • Initial success: 8/14 patients were able to discontinue ART following one or more STIs, maintaining a VL less than 500 copies/mL • However, all but 3 of these patients subsequently lost virologic control Walker B. State of the Art Lecture and Summary. 8th CROI, Session #37.

  32. STIs during Chronic Infection • Results variable but less encouraging • No consistent improvement in virologic control • Significant proportion fail to regain CD4 count prior to treatment interruptions • May nonetheless prove useful for other reasons

  33. Potential Benefits of Treatment during PHI • Suppress initial burst of viremia • ? alter viral set-point • Decrease viral evolution • Preserve CD4 lymphocytes (both absolute number and HIV-specific) • Potentially decrease risk of transmission • Possibly allow for therapy to be stopped

  34. Potential Risks of Treatment during PHI • Drug toxicity • Costs of possible lifelong therapy • Starting therapy in patients who may never had needed it • Early development of resistance • Limited evidence to date of clinical benefit

  35. Treatment of PHI: Recommendations • Patients should be informed of the risks, benefits, and uncertainties • For treatment, consider two nucleoside analogues plus a protease inhibitor or an NNRTI (consider US treatment guidelines) • STI strategies remain experimental • Consider referrals to studies when possible

  36. Primary HIV Infection: Conclusions • PHI is under-diagnosed • May represent a critical opportunity to intervene • A high index of suspicion, recognition of key signs & symptoms, and lab testing are required for the diagnosis • ART may provide opportunity for improved long-term virologic control of HIV • Ongoing studies should clarify the potential role of treatment during PHI, including Structured Treatment Interruptions

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