1. Acute HIV Infection September 13, 2007 H. Nina Kim MD, MS I-TECH/University of Washington Distance Learning Clinical Seminar Series

2. 2 Case  25 yo sexually active woman presents with a 3- week hx fever, fatigue, HA, mild sore throat.  On physical exam, the patient is alert & oriented.  T 38.2 C. A maculopapular rash is present over trunk & face. A few ulcers are seen on soft palate.  Cervical lymph nodes are slightly enlarged, and her neck is stiff. Pelvic exam shows mild cervicitis.  WBC 3.6, Hct 34%, platelets 90,000. Monospot & serum RPR are negative. A cervical swab reveals Neisseria gonorrhoeae by DNA probe.

3. 3 Case Which of the following is the most likely diagnosis?  Acute HIV infection  Cytomegalovirus mononucleosis  Primary herpes simplex virus infection  Secondary syphilis  Disseminated gonococcal infection

4. 4 Acute HIV Infection  Epidemiology  Clinical Features  Differential  Diagnosis  (Treatment)

5. Epidemiology  4.3 million people newly infected with HIV in 2006 per UNAIDS estimates

6. 6 Important to capture acute HIV infection  Early entry into clinical care &/or study  Public health implications – Reduce secondary transmission: Patients with acute HIV infection (AHI) higher-risk behavior AHI index cases reported 4.85 partners per 6 months CHI “controls” reported 1.1 partners per 6 months Pilcher et. al. CROI 2006; Abstract #371. Patients with AHI have higher viral levels in plasma and genital secretions

7. 7 Risk of HIV Transmission by Stage of Infection Cohen & Pilcher. J Infect Dis 2005;191(9):1391-3..

8. 8 High Per-Partnership Transmission Study Attack RateAvg Exposure Wawer, JID 200510/23 (43%)20 weeks Pilcher CROI 20066/12 (50%)10 weeks Brooks AIDS 20063/13 (23%)‘single’ acts

9. 9 A Missed Opportunity…  But detection of acute HIV not common:  Among 46 prospectively identified recent seroconverters, 41 (89%) recalled symptoms of acute retroviral syndrome. Only 25% were diagnosed acute HIV at the 1 st presentation. Schacker et. al. Ann Intern Med 1996;125:257.  In another study, among 50 recent seroconverters who were symptomatic & presented to medical care, only 8 (16%) correctly diagnosed. Celum et. al. J Infect Dis 2001;183:23.

10. 10 Why Missed?  Wide range in clinical manifestations  Non-specific signs & symptoms  Lack of clinical suspicion  Asking difficult questions: You need to elicit exposure history!  Diagnostic Testing:  Not readily available  Lack of understanding

11. 11 A “Flu-like” Illness  1985, a “mononucleosis-like” syndrome preceding seroconversion described  11 of 12 men who had sex w/ men (MSM)  Sudden onset, lasting from 3-14 days  Clinical features:  Fever/sweats  Headaches, malaise, anorexia  Lethargy, myalgias/arthralgias  Generalized LAN  Rash: “erythematous maculopapular truncal eruption” DA Cooper et.al., Lancet 1985;1:537.

12. 12 Signs & Symptoms JO Kahn & B Walker, N Engl J Med 1998;339:35.

13. JO Kahn & B Walker, N Engl J Med 1998;339:36 JO Kahn & B Walker, N Engl J Med 1998;339:36.

17. 17 Differential Diagnosis  Infectious mononucleosis (primary acute EBV, CMV)  Secondary syphilis  Hepatitis A or B (acute infection)  Malaria  Typhoid fever  Toxoplasmosis  Aseptic meningitis  Viral pharyngitis; influenza  Drug reaction

18. 18 E Daar et.al., Ann Intern Med 2001;134:25-9 E Daar et.al., Ann Intern Med 2001;134:25-9.

19. 19 Predictors of Acute HIV  Prospective study of 1053 HIV-negative female sex workers in Mombasa, Kenya  N=162 women seroconverted  Clinical scoring system: ≥2 S/Sx  51% sensitivity & 83% specificity for detecting acute HIV L Lavreys et.al., Clin Infect Dis 2000;30:488 L Lavreys et.al., Clin Infect Dis 2000;30:488. Symptom or SignAdjusted OR (95% CI) Fever2.8 (1.8-4.2) Vomiting4.8 (2.9-8.1) Diarrhea3.1 (1.8-5.4) Headache2 (1.3-3) Myalgia2.8 (1.6-4.7) Skin Rash2.1 (1-4.2) Too sick to work4 (2.7-6.1) Sick days (>7)7.4 (4.1-13.1) Inguinal LAN9.5 (4.3-13.1) Vaginal Candida2.7 (1.7-4.2)

20. 20 Timeline of Events Viral Set point

21. 21 Diagnostic Tests  Acute or Primary HIV Infection  Negative ELISA + positive HIV viral RNA  Negative ELISA + positive p24 antigen  Early HIV Infection  Positive ELISA + indeterminate Western Blot  Positive ELISA + evolving Western Blot  Positive ELISA + negative “detuned” Ab test  Positive ELISA + negative ELISA x 6 mon ago

22. 22 Time Course Pilcher C et al, J Clin Investigation 2004;113:937.

23. 23 E Fiebig et.al., AIDS 2003;17:1871-9 E Fiebig et.al., AIDS 2003;17:1871-9. Evolution of Tests during Acute  Early HIV Infection

24. 24 Evolving Western Blots TC Quinn, JAMA 1997;278:59.

25. 25 HIV p24 Antigen CD Pilcher et. al, Ann Intern Med 2002;136:488.

26. 26 HIV Viral Load TW Schacker et al, Ann Intern Med 1998;128:615.

27. 27 CD Pilcher, et. al. JAMA 2002;288:216. Screening by Pooled HIV RNA

28. A Individual testing on 10 specimens 10 pools of 10 screened 20 Screening Pools Tested N=2000 Resolution Testing

29. 29 Low Complexity Testing Options for Resource-Limited Settings  Dried blood spots with central HIV RNA testing in major lab centers (Uganda, Brazil)  p24 Ag EIAs  Fourth generation EIA (p24 Ag/Ab combo)  Dual rapid antibody testing  Point-of-care rapid NAAT …

30. 30 Viral Setpoints & Outcome Multicenter AIDS Cohort Study RH Lyles et. al. J Infect Dis 2000;181:878.

31. 31 Prospective cohort study of Kenyan women L Lavreys et. al. Clin Infect Dis 2006;42:1333. Symptoms of Acute Retroviral Syndrome & Outcome

32. 32 Why Study Acute HIV Infection? Because Treatment may:  Alter initial viral set point & delay disease progression  Lower viral diversification  Reduce severity of acute retroviral sx’s  Diminish 2° HIV transmission  Preserve critical immune function

33. 33 But Treatment of Acute HIV may also come with Risks:  Medication toxicities extended over longer duration  Impact on quality of life  Drug resistance  ? Duration of therapy

34. 34 Remaining Questions  Can early treatment & viral suppression provide longterm immune preservation?  How soon must Tx be initiated to observe sustained immunologic benefits?  What is optimal duration of Tx?  Safety & adherence in this early group?

35. 35 Signs & Symptoms Suggesting Acute HIV? Most predictive Fever Rash Myalgias/Arthralgias Lymphadenopathy Pharyngitis HIV Ab Test(s), p24 Ag, HIV viral RNA Less suggestive Cough Coryza Helpful Leukopenia, Thrombocytopenia Risk Factors & Exposures Unprotected Sexual Intercourse (oral, anal, vaginal) Sharing needles (injection drug use) Has HIV-infected sexual or IVDU partner Men who have sex with men (MSM) Partner of MSM Hx STDs or ulcerative oral/genital lesions