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

• Treatment Options

• Conclusions & Recommendations

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

Exposure to HIV atmucosal 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

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Pla

sma

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A (

cop

ies/

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)

Plasma RNA Viral Load

CD4 Cell Count

4-8 Weeks Up to 12 Years 2-3 Years

CD

4 Cell C

ount (cells/m

m³)

1,000

500

Primary HIV Infection: Pathogenesis

Symptoms

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

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.

Clinical Approach to the Diagnosis of Primary HIV Infection

• Exposure

• Signs & Symptoms

• Laboratory Testing

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

Percutaneous (blood)1 0.3%

Mucocutaneous (blood)2 0.09%

Receptive anal intercourse3 0.3 - 3%

Insertive anal intercourse4 0.06%

Receptive vaginal intercourse5 0.1 – 0.2%

Insertive vaginal intercourse6 0.03 – 0.14%

Receptive oral (male)7 0.06%

Female-female orogenital8 4 case reports

IDU needle sharing9 0.67%

Vertical (no prophylaxis)10 24%

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.

Primary HIV Infection: Common Signs & Symptoms

44

52

55

57

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86

0 10 20 30 40 50 60 70 80 90 100

adenopathy

pharyngitis

headache

rash

myalgias

lethargy

fever

N = 160 patients with PHI inGeneva, Seattle, and Sydney

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

% of patients

21

40

45

10

15

24

0 20 40 60 80 100

transaminitis

leukopenia

thrombocytopenia

genital ulcers

oral ulcers

aseptic meningitis

Primary HIV Infection: Other Signs & Symptoms

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

% of patients

Primary HIV Infection

Rash Mucosal Lesions

Trunk and face > limbsSmall pink macules

Oral ulcers, thrush

(Kahn, NEJM, 1998)

Oral Ulcers in Acute HIV Infection

From: Walker, B. 40th IDSA, Chicago 2002.

Genital Ulcer in Acute HIV Infection

From: Walker, B. 40th IDSA, Chicago 2002.

Diagnostic Testing for PHIDiagnostic Testing for PHI

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_HIV

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IV-1

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Exposure

P24 +

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Symptoms

Days

HIV RNA

Ab

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.

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.

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

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.

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

1

10

100

1,000

10,000

100,000

1,000,000

10,000,000

Pla

sma H

IV R

NA

(co

pie

s/m

L)

Plasma RNA Viral Load

CD4 Cell Count

4-8 Weeks Up to 12 Years 2-3 Years

CD

4 count (cells/m

m³)

1,000

500

Primary HIV Infection: Pathogenesis

Viral set point

Anti-HIVT-cell response

Sero-conversionAntibody response

A lot of important stuff happens here

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

Loss of HIV-specific Cytotoxic T-Lymphocyte Response (CTL)

Picture

Antigen-Presenting Cells

Activated CD4 Cell

Activated CD8 Pre CTL CD8 Cell

HIV-Infected CD4

Mature CD8 CTL

CD4 CellHIV

HIV

Lymphokines

Adapted from: Cohen DE, Walker BD. Clin Infect Dis 2001;32:1756-68

Slide courtesy David Spach, MD

Cellular Immune Response to Acute HIV Infection

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0 1 2 3 4 5 6 7 8Time

HIV

RN

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Weak CTL

Moderate CTL

Strong CTL

Rapid Progression

Moderate Progression

Slow Progression

From: Walker BD. Nature 2000;407:313-4.

6 months

Acute HIV

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

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

Structured Treatment Interruptions

Structured Treatment Interruptions

What’s the Evidence?

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.

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.

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.

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

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

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

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

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