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

4. Plasma RNA Viral Load CD4 Cell Count 4-8 WeeksUp to 12 Years2-3 Years CD4 Cell Count (cells/mm³) 1,000 500 Primary HIV Infection: Pathogenesis Symptoms

5. Epidemiology of Primary HIV Infection United States: –44,000 cases per year 1 –120 cases per day Globally: 14,000 cases/day 2 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) Percutaneous (blood) 1 0.3% Mucocutaneous (blood) 2 0.09% Receptive anal intercourse 3 0.3 - 3% Insertive anal intercourse 4 0.06% Receptive vaginal intercourse 5 0.1 – 0.2% Insertive vaginal intercourse 6 0.03 – 0.14% Receptive oral (male) 7 0.06% Female-female orogenital 8 4 case reports IDU needle sharing 9 0.67% Vertical (no prophylaxis) 10 24%

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 Vanhems P et al. AIDS 2000; 14:0375-0381. % of patients

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

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

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

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

18. Diagnostic Testing for PHI 1 mil 100,000 10,000 1,000 100 10 + _ HIV RNA HIV-1 Antibodies Exposure P24 + 020304050 Symptoms Days HIV RNA Ab

19. Diagnostic Testing: Viral Load More sensitive than HIV antibody or p24 Ag test 3 Positive one to three weeks before antibody test 1 Typically high level, e.g. greater than 50,000-100,000 copies/mL 2,3 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.

20. 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 infection 1 1. Kahn JO, Walker BD. N Engl J Med. 1998;339:33-39.

21. 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

22. 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.

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

24. Plasma RNA Viral Load CD4 Cell Count 4-8 WeeksUp to 12 Years2-3 Years CD4 count (cells/mm³) 1,000 500 Primary HIV Infection: Pathogenesis Viral set point Anti-HIV T-cell response Sero-conversion Antibody response A lot of important stuff happens here

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

26. Loss of HIV-specific Cytotoxic T-Lymphocyte Response (CTL) Picture Antigen-Presenting Cells Activated CD4 Cell Activated CD8 Pre CTLCD8 Cell HIV-Infected CD4 Mature CD8 CTL CD4 Cell HIV Lymphokines Adapted from: Cohen DE, Walker BD. Clin Infect Dis 2001;32:1756-68

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

28. 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

29. 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

30. Structured Treatment Interruptions

31. What’s the Evidence?

32. 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.

33. 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.

34. 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.

35. 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

36. 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

37. 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

38. 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

39. 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