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Acute HIV infection
Christian B. Ramers, MD
Duke Medicine-Pediatrics Residency Program
Overview
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Definition
Epidemiology
Clinical Features
Lab Diagnosis/Virological Characteristics
Treatment options
Tanzania’s policies
Cases
What is Acute Anti-retroviral Syndrome?
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Earliest stage if HIV infection usually occurring days
to weeks after exposure, but encompasses any infection
recognized prior to seroconversion
Characterized by:
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Flu-like or ‘Mono-like’ illness
HIV RNA >100,000 copies/mL
Widespread dissemination of HIV in lymphoid tissues
Negative HIV Antibody by ELISA
Extremely high infectivity
Median time to seroconversion is 25 days, but can be
as long as 6 months
Presenting Signs/Symptoms
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Roughly 75% (50-90%) will have symptoms
Usually appear days to weeks after exposure
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Fever (80-90%), fatigue (70-90%), anorexia (30-60%)
Rash (40-80%)– often erythematous maculopapular
Pharyngitis (50-70%)
Generalized lymphadenopathy (40-70%)
Mucocutaneous Ulceration (oral 10-20%, genital 5-15%)
Headache (32-70%), often retroorbital with meningismus
Neurologic: Aseptic meningitis (24%), radiculitis, myelitis
May present with OI, thrush, zoster (if CD4 depressed)
* Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39
Pathophysiology
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Langerhans cells (submucosal dendritic cells) are first to
be infected via CD4 and CCR5 receptors
Dendritic cells then cluster at local lymph nodes and
pass on virus preferentially to memory
Animal models show HIV in internal iliac LN’s by day 2
Viremia develops within 4-11 days and proceeds
uncontrolled reaching >100,000 copies/mL
Initial antibody responses are weak and control of
viremia is mostly by potent CD8 cytotoxic cells
Viral ‘set point’ reached by 6 months with significant
prognostic value
From www.HIV Webstudy.com – University of Washington 2006
Acute HIV syndrome
Data from Vanhems et al 2000,
showing clinical features of 160
pts with acute HIV infection
compiled from Geneva, Seattle,
and Sydney
Establishment of viral ‘set
point’. Modified from
Walker BD, Goulder PJ.
AIDS. Escape from the
immune system. Nature.
2000;407:313-4.
Laboratory Evaluation
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Must send plasma HIV RNA RT-PCR as well as
ELISA to confirm diagnosis.
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RNA-PCR available at KCMC for TSh 5,000
RT-PCR positive within 11 days of infection
Any positive Ab or RT-PCR should be immediately
confirmed to avoid conveying false positive results
Viral load typically very high (>100,000 copies/mL)
Many associated Lab abnormalities:
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Anemia, Leukopenia (40%), Thrombocytopenia (45%)
Transaminitis (21%), CSF pleiocytosis (24%)
Hyponatremia?, high total protein?
* Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39
Laboratory Evaluation - continued
*United Republic of Tanzania – Ministry of Health. National AIDS Control Programme. National Guidelines for
the Clinical Management of HIV and AIDS. Second Edition, April 2005
Laboratory Evaluation - continued
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Baseline lab evaluation is typically sent at initial
outpatient HIV clinic visit:
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Confirmatory RT-PCR and ELISA if not done
Viral Genotyping is recommended
• (up to 15-20% of acute HIV caused by resistant strains)
Baseline CBC, Chem 7, GI Panel, Lipids
PPD, Hepatitis Serologies, Toxo IgG
CXR, EKG, Pap smear
* Hammer SM. Clinical Practice: Management of Newly Diagnosed HIV Infection. NEJM 2005; 353 (16): 1702-10
Index of Suspicion is Key!!
Differential Diagnosis Includes:
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Malaria
Primary CMV
Drug reaction
Infectious Mononucleosis
(EBV)
Viral Hepatitis (A, B, C)
Primary HSV
Influenza
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Trypanosomiasis
Parainfluenza
RSV
Severe GAS pharyngitis
Secondary Syphilis
Toxoplasmosis
Rubella
Rickettsial diseases
Initial Counseling
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Patients need extensive support during initial
infection, especially to allow acceptance
Safe sex pracitices must be reinforced since patients
are most infectious during acute infection
Emphasis should be placed on HIV being chronic
infection which should not be life-limiting
Initiation of ART is a highly individualized decision
between HIV provider and patient taking in to
account social support, patient readiness, current
recommendations on viral load/CD4 parameters
Clinical Course
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Patients are typically symptomatic for 14 days,
but lymphadenopathy and some laboratory
abnormalities may persist longer
In absence of ART viral load decreases in 8-12
weeks to ‘set point’ usually 1-10,000 copies/mL
Diagnosis may be missed in 75% of cases
Asymptomatic latent phase of infection ensues
over next 5-10 years with gradual depletion of
CD4/CD8 cells with destruction of lymph node
architecture
* Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39
Duration of Latent Period – WHO stage I
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Cohort studies from Haiti and Kenya suggest a 4
to 7 yr asymptomatic latent period prior to
clinical AIDS (shorter than in US – 8-10 yrs)
Acceleration of immuno-suppression in Africa
thought to be due to activation of HIV-infected
immune cells by Tuberculosis, helminthitic or
parasitic infections
Typical course of human immunodeficiency virus (HIV) infection
Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663
To treat or not to treat?
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Rosenberg and co-workers* have demonstrated that
treating primary HIV-1 infection allows for the
maintenance of T-Helper cell responses to HIV-1-specific
antigens, whereas these responses are more difficult to
demonstrate in similarly treated, chronically infected
persons. Given the knowledge that a small, slowly
decaying latent infectious reservoir is established very
early in the course of HIV-1 infection, the maintenance of
these immune responses may be critical if the ultimate
goal of immune control of HIV-1 is to be achieved.
* Rosenberg E, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific
CD4+ T cell responses associated with control of viremia. Science 1997;278:1447-50
Advantages and Disadvantages
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Advantages:
• Decrease in duration/severity of primary illness
• May lower initial viral load set point
• Slows disease progression
• Enhances recovery of CD4 cell populations
• Early therapy may reduce rates of viral mutations
• Decreases viral transmission
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10-20X more infectious in acute stage
50% of transmission due to acute hyperinfectiousness
Disadvantages:
• Side effects may adversely affect quality of life
• Establishing adherence may be difficult in acute illness
• More ARV exposure  more ARV resistance
From HIV Webstudy – University of Washington 2006
Who gets ARV’s in Tanzania?
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d4T/3TC/NVP (triomune)
AZT/3TC/NVP
d4T/3TC/EFV (if Tb/anemia)
AZT/3TC/EFV (if Tb)
AZT/ddI/Lop-r
ABC/ddI/Lop-r
*United Republic of Tanzania – Ministry of Health. National AIDS Control Programme. National Guidelines for
the Clinical Management of HIV and AIDS. Second Edition, April 2005
Revised WHO clinical staging of HIV
Revised WHO clinical staging of HIV
Long-term Non-Progressors (LTNP’s)
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Only compose 5% of HIV infected pts
Characterized by absence of progression from HIV infection
to AIDS even in the absence of ART for > 10 years
Have been observed to have more preserved anti-HIV CD-4
proliferative responses and higher CD-8 Cytotoxic responses
Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663
Pantaleo G, et al. N Eng J Med 1995;332: 209-16; Cao Y, et al. N EngI J Med 1994:332:201-8; Haynes B, et al. Science 1996;271:324-7.
HAART in 2007
2006 – >25 antiretrovirals available
Atripla – approved July 2006: fixed-dose
combination of Efavirenz, Emtricitabine,
Tenofovir; i tab PO QD
Recommended ART Regimens in Tanzania
Reason for Optimism
Initial Dx (9/6/06)
ID clinic (9/20/06)
CD4+ = 66
CD4+ = 188
VL = > 750,000 copies/mL VL = < 100 copies/mL
Case Presentation#1
A 27 yo previously healthy man presents to casualty
complaining of 2 d of fever, sore throat, and generalized
body malaise and you note cervical and axillary LAD, mild
meningismus and a diffuse maculopapular rash on PEX. On
further history, he notes an episode of unprotected
intercourse roughly 3 wks prior. Acute HIV infection is
suspected. Which of the following is true regarding acute
HIV?
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B.
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< 5% of acute HIV results in clinical illness
>80% of symptomatic acute HIV presents with aseptic meningitis.
Patients recently infected with HIV typically have viral loads in
excess of 50,000 copies/mL within 4 weeks of infection
A negative HIV antibody and a viral load of 2,000 copies/mL is
consistent with acute HIV infection
Case Presentation#1
A 27 yo previously healthy man presents to casualty
complaining of 2 d of fever, sore throat, and generalized
body malaise and you note cervical and axillary LAD, mild
meningismus and a diffuse maculopapular rash on PEX. On
further history, he notes an episode of unprotected
intercourse roughly 3 wks prior. Acute HIV infection is
suspected. Which of the following is true regarding acute
HIV?
A.
B.
C.
D.
< 5% of acute HIV results in clinical illness
>80% of symptomatic acute HIV presents with aseptic meningitis.
Patients recently infected with HIV typically have viral loads in
excess of 50,000 copies/mL within 4 weeks of infection
A negative HIV antibody and a viral load of 2,000 copies/mL is
consistent with acute HIV infection
Acute HIV syndrome
 Viremia detectable by RT-PCR within 4-11 days
 Roughly 40-90% of acute infections have symptomatic
phase lasting 1-2 wks within 28 days of initial exposure
 High Viral Loads (>100K) are reached within 2-3
weeks but fall by 6 months to a ‘set point’ largely
determined by strength of CD8 cytotoxic T-cell
response, which may predict progression
 Dx only by RT-PCR as sero-conversion takes 1-3 mos
 Pts are HIGHLY infectious in acute phase making
early dx and counseling essential to prevent spread
 Initiating therapy during this period is controversial
with no established standard of care
References
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CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm, Additional
Resources: http://www.hivatis.org , http://www.hivinsite.org ,
http://www.aidsinfo.nih.gov
Merson, MH. The HIV-AIDS Pandemic at 25—The Global Response.
NEJM, 2006; 354: 2414-2417
Hammer SM. Management of Newly Diagnosed HIV Infection. NEJM
2005; 353:1702-10
Kim JY and Farmer P. AIDS in 2006 – Moving Toward One World, One
hope? NEJM 2006; 355(7): 645-7
UNAIDS – 2006 report on the Global AIDS epidemic
Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39
Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663
Rosenberg E. et al. Vigorous HIV-1-specific CD4+ T cell responses
associated with control of viremia. Science 1997;278:1447-50
Pantaleo G, et al. N Eng J Med 1995;332: 209-16
Cao Y, et al. N EngI J Med 1994:332:201-8
Haynes B, et al. Science 1996;271:324-7.
Clinical & Educational Resources
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UW Case-based HIV learning site: http://depts.washington.edu/hivaids/
CDC PEP guidelines:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm
Hopkins HIV guide: http://www.hopkins-hivguide.org/
MGH/BWH image database: http://www.idimages.org/
Baylor Pediatric AIDS Initiative: http://bayloraids.org/
Hopkins online lectures ‘Principles of Anti-Retroviral Therapies’:
http://www.ccghe.jhmi.edu/CCG/distance/HIV_Courses/art.asp#Principles
IDSA/HIVMA practice guidelines:
http://www.idsociety.org/HIVMA_Template.cfm?Section=Practice_Guidelines2
CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm ,
http://www.cdc.gov/hiv/topics/surveillance/resources/slides/index.htm
Additional Resources: http://www.hivatis.org
Additional Resources: http://www.hivinsite.org
Additional Resources: http://www.aidsinfo.nih.gov