Acute HIV Infection

September 13, 2007

H. Nina Kim MD, MS

I-TECH/University of Washington

Distance Learning Clinical Seminar Series

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

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

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Acute HIV Infection

Epidemiology

Clinical Features

Differential

Diagnosis

(Treatment)

Epidemiology 4.3 million people newly infected with HIV in 2006

per UNAIDS estimates

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

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Risk of HIV Transmission byStage of Infection

Cohen & Pilcher. J Infect Dis 2005;191(9):1391-3..

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High Per-Partnership Transmission

Study Attack Rate Avg Exposure

Wawer, JID 2005 10/23 (43%) 20 weeks

Pilcher CROI 2006 6/12 (50%) 10 weeks

Brooks AIDS 2006 3/13 (23%) ‘single’ acts

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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 1st 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.

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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

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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.DA Cooper et.al., Lancet 1985;1:537.

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Signs & Symptoms

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

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

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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

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E Daar et.al., Ann Intern Med E Daar et.al., Ann Intern Med 2001;134:25-92001;134:25-9.

88

60

58

50

28

50

26

21

32

13

3818

0 20 40 60 80 100

Fever

Myalgia

Rash

Night sweats

Arthralgias

Nasalcongestion

(%)

non-AHIAHI

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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 L Lavreys et.al., Clin Infect Dis 2000;30:4882000;30:488.

Symptom or Sign Adjusted OR (95% CI)

Fever 2.8 (1.8-4.2)

Vomiting 4.8 (2.9-8.1)

Diarrhea 3.1 (1.8-5.4)

Headache 2 (1.3-3)

Myalgia 2.8 (1.6-4.7)

Skin Rash 2.1 (1-4.2)

Too sick to work 4 (2.7-6.1)

Sick days (>7) 7.4 (4.1-13.1)

Inguinal LAN 9.5 (4.3-13.1)

Vaginal Candida 2.7 (1.7-4.2)

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Timeline of Events

Viral Set point

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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

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Time Course

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

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E Fiebig et.al., AIDS 2003;17:1871-9E Fiebig et.al., AIDS 2003;17:1871-9.

Evolution of Tests during Acute Early HIV Infection

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Evolving Western Blots

TC Quinn, JAMA 1997;278:59.TC Quinn, JAMA 1997;278:59.

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HIV p24 Antigen

CD Pilcher et. al, Ann Intern Med 2002;136:488.CD Pilcher et. al, Ann Intern Med 2002;136:488.

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HIV Viral Load

TW Schacker et al, Ann Intern Med 1998;128:615.TW Schacker et al, Ann Intern Med 1998;128:615.

27CD Pilcher, et. al. JAMA 2002;288:216.CD Pilcher, et. al. JAMA 2002;288:216.

Screening by Pooled HIV RNA

A

Individual testing on 10 specimens

10 pools of 10 screened

20 Screening Pools Tested

N=2000

Resolution Testing

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Low Complexity TestingOptions 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 …

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Viral Setpoints & Outcome

MulticenteMulticenter AIDS r AIDS Cohort Cohort StudyStudy

RH Lyles et. al. RH Lyles et. al. J Infect Dis J Infect Dis 2000;181:878.2000;181:878.

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Prospective Prospective cohort study of cohort study of Kenyan womenKenyan women

L Lavreys et. al. Clin L Lavreys et. al. Clin Infect Dis Infect Dis 2006;42:1333.2006;42:1333.

Symptoms of Acute Retroviral Syndrome & Outcome

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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

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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

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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?

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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