Acute HIV infectionAcute HIV infection

Christian B. Ramers, MDChristian B. Ramers, MD

Duke Medicine-Pediatrics Residency Duke Medicine-Pediatrics Residency ProgramProgram

OverviewOverview

• DefinitionDefinition• EpidemiologyEpidemiology• Clinical FeaturesClinical Features• Lab Diagnosis/Virological Lab Diagnosis/Virological

CharacteristicsCharacteristics• Treatment optionsTreatment options• Tanzania’s policiesTanzania’s policies• CasesCases

What is Acute Anti-retroviral What is Acute Anti-retroviral Syndrome?Syndrome?

• Earliest stage if HIV infection usually occurring Earliest stage if HIV infection usually occurring days to weeks after exposure, but encompasses days to weeks after exposure, but encompasses any infection recognized prior to seroconversionany infection recognized prior to seroconversion

• Characterized by: Characterized by: • Flu-like or ‘Mono-like’ illnessFlu-like or ‘Mono-like’ illness• HIV RNA >100,000 copies/mLHIV RNA >100,000 copies/mL• Widespread dissemination of HIV in lymphoid Widespread dissemination of HIV in lymphoid

tissuestissues• Negative HIV Antibody by ELISANegative HIV Antibody by ELISA• Extremely high infectivityExtremely high infectivity

• Median time to seroconversion is 25 days, but Median time to seroconversion is 25 days, but can be as long as 6 monthscan be as long as 6 months

Presenting Signs/SymptomsPresenting Signs/Symptoms• Roughly 75% (50-90%) will have symptomsRoughly 75% (50-90%) will have symptoms• Usually appear days to weeks after exposureUsually appear days to weeks after exposure

• Fever (80-90%), fatigue (70-90%), anorexia (30-Fever (80-90%), fatigue (70-90%), anorexia (30-60%)60%)

• Rash (40-80%)– often erythematous maculopapularRash (40-80%)– often erythematous maculopapular• Pharyngitis (50-70%)Pharyngitis (50-70%)• Generalized lymphadenopathy (40-70%)Generalized lymphadenopathy (40-70%)• Mucocutaneous Ulceration (oral 10-20%, genital 5-Mucocutaneous Ulceration (oral 10-20%, genital 5-

15%)15%)• Headache (32-70%), often retroorbital with Headache (32-70%), often retroorbital with

meningismusmeningismus• Neurologic: Aseptic meningitis (24%), radiculitis, Neurologic: Aseptic meningitis (24%), radiculitis,

myelitismyelitis• May present with OI, thrush, zoster (if CD4 May present with OI, thrush, zoster (if CD4

depressed)depressed)* Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

PathophysiologyPathophysiology• Langerhans cells (submucosal dendritic cells) are Langerhans cells (submucosal dendritic cells) are

first to be infected via CD4 and CCR5 receptorsfirst to be infected via CD4 and CCR5 receptors• Dendritic cells then cluster at local lymph nodes and Dendritic cells then cluster at local lymph nodes and

pass on virus preferentially to memory pass on virus preferentially to memory • Animal models show HIV in internal iliac LN’s by day Animal models show HIV in internal iliac LN’s by day

22• Viremia develops within 4-11 days and proceeds Viremia develops within 4-11 days and proceeds

uncontrolled reaching >100,000 copies/mLuncontrolled reaching >100,000 copies/mL• Initial antibody responses are weak and control of Initial antibody responses are weak and control of

viremia is mostly by potent CD8 cytotoxic cellsviremia is mostly by potent CD8 cytotoxic cells• Viral ‘set point’ reached by 6 months with Viral ‘set point’ reached by 6 months with

significant prognostic valuesignificant prognostic value

From www.HIV Webstudy.com – University of Washington 2006

Acute HIV syndromeAcute HIV syndrome

Data from Vanhems et al Data from Vanhems et al 2000, showing clinical 2000, showing clinical features of 160 pts with features of 160 pts with acute HIV infection acute HIV infection compiled from Geneva, compiled from Geneva, Seattle, and SydneySeattle, and Sydney

Establishment of viral Establishment of viral ‘set point’. Modified ‘set point’. Modified from Walker BD, Goulder from Walker BD, Goulder PJ. AIDS. Escape from PJ. AIDS. Escape from the immune system. the immune system. Nature. 2000;407:313-4.Nature. 2000;407:313-4.

Laboratory EvaluationLaboratory Evaluation• Must send plasma HIV RNA RT-PCR as well as ELISA Must send plasma HIV RNA RT-PCR as well as ELISA

to confirm diagnosis.to confirm diagnosis.• RNA-PCR available at KCMC for TSh 5,000RNA-PCR available at KCMC for TSh 5,000

• RT-PCR positive within 11 days of infectionRT-PCR positive within 11 days of infection• Any positive Ab or RT-PCR should be immediately Any positive Ab or RT-PCR should be immediately

confirmed to avoid conveying false positive resultsconfirmed to avoid conveying false positive results• Viral load typically Viral load typically veryvery high (>100,000 copies/mL) high (>100,000 copies/mL)• Many associated Lab abnormalities:Many associated Lab abnormalities:

• Anemia, Leukopenia (40%), Thrombocytopenia Anemia, Leukopenia (40%), Thrombocytopenia (45%)(45%)

• Transaminitis (21%), CSF pleiocytosis (24%)Transaminitis (21%), CSF pleiocytosis (24%)• Hyponatremia?, high total protein?Hyponatremia?, high total protein?

* Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

Laboratory Evaluation - continuedLaboratory 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 - continuedLaboratory Evaluation - continued• Baseline lab evaluation is typically sent at Baseline lab evaluation is typically sent at

initial outpatient HIV clinic visit:initial outpatient HIV clinic visit:• Confirmatory RT-PCR and ELISA if not doneConfirmatory RT-PCR and ELISA if not done• Viral Genotyping is recommended Viral Genotyping is recommended

• (up to 15-20% of acute HIV caused by (up to 15-20% of acute HIV caused by resistant strains) resistant strains)

• Baseline CBC, Chem 7, GI Panel, LipidsBaseline CBC, Chem 7, GI Panel, Lipids• PPD, Hepatitis Serologies, Toxo IgGPPD, Hepatitis Serologies, Toxo IgG• CXR, EKG, Pap smearCXR, EKG, Pap smear

* Hammer SM. Clinical Practice: Management of Newly Diagnosed HIV Infection. NEJM 2005; 353 (16): 1702-10

Index of Suspicion is Key!!Index of Suspicion is Key!!

• MalariaMalaria• Primary CMVPrimary CMV• Drug reactionDrug reaction• Infectious Infectious

Mononucleosis (EBV) Mononucleosis (EBV) • Viral Hepatitis (A, B, Viral Hepatitis (A, B,

C)C)• Primary HSVPrimary HSV• InfluenzaInfluenza

• TrypanosomiasisTrypanosomiasis• Parainfluenza Parainfluenza • RSVRSV• Severe GAS Severe GAS

pharyngitispharyngitis• Secondary SyphilisSecondary Syphilis• ToxoplasmosisToxoplasmosis• RubellaRubella• Rickettsial diseasesRickettsial diseases

Differential Diagnosis Differential Diagnosis Includes:Includes:

Initial CounselingInitial Counseling• Patients need extensive support during initial Patients need extensive support during initial

infection, especially to allow acceptanceinfection, especially to allow acceptance• Safe sex pracitices Safe sex pracitices mustmust be reinforced since be reinforced since

patients are most infectious during acute patients are most infectious during acute infectioninfection

• Emphasis should be placed on HIV being Emphasis should be placed on HIV being chronic infection which chronic infection which should not be life-should not be life-limitinglimiting

• Initiation of ART is a highly individualized Initiation of ART is a highly individualized decision between HIV provider and patient decision between HIV provider and patient taking in to account social support, patient taking in to account social support, patient readiness, current recommendations on viral readiness, current recommendations on viral load/CD4 parameters load/CD4 parameters

Clinical CourseClinical Course• Patients are typically symptomatic for 14 Patients are typically symptomatic for 14

days, but lymphadenopathy and some days, but lymphadenopathy and some laboratory abnormalities may persist laboratory abnormalities may persist longerlonger

• In absence of ART viral load decreases in In absence of ART viral load decreases in 8-128-12 weeks to ‘set point’ usually 1-10,000 weeks to ‘set point’ usually 1-10,000 copies/mLcopies/mL

• Diagnosis may be missed in 75% of cases Diagnosis may be missed in 75% of cases • Asymptomatic latent phase of infection Asymptomatic latent phase of infection

ensues over next 5-10 years with gradual ensues over next 5-10 years with gradual depletion of CD4/CD8 cells with depletion of CD4/CD8 cells with destruction of lymph node architecturedestruction of lymph node architecture

* * Kahn JO, and Walker BD; Acute HIV Infection NEJM 1998; 339: 33-39

Duration of Latent Period – WHO stage Duration of Latent Period – WHO stage II

• Cohort studies from Haiti and Kenya Cohort studies from Haiti and Kenya suggest a 4 to 7 yr asymptomatic latent suggest a 4 to 7 yr asymptomatic latent period prior to clinical AIDS (shorter than period prior to clinical AIDS (shorter than in US – 8-10 yrs)in US – 8-10 yrs)

• Acceleration of immuno-suppression in Acceleration of immuno-suppression in Africa thought to be due to activation of Africa thought to be due to activation of HIV-infected immune cells by HIV-infected immune cells by Tuberculosis, helminthitic or parasitic Tuberculosis, helminthitic or parasitic infectionsinfections

Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663

Typical course of human immunodeficiency virus (HIV) infection

To treat or not to treat?To treat or not to treat? Rosenberg and co-workers* have demonstrated Rosenberg and co-workers* have demonstrated

that treating primary HIV-1 infection allows for that treating primary HIV-1 infection allows for the maintenance of T-Helper cell responses to the maintenance of T-Helper cell responses to HIV-1-specific antigens, whereas these HIV-1-specific antigens, whereas these responses are more difficult to demonstrate in responses are more difficult to demonstrate in similarly treated, chronically infected persons. similarly treated, chronically infected persons. Given the knowledge that a small, slowly Given the knowledge that a small, slowly decaying latent infectious reservoir is decaying latent infectious reservoir is established very early in the course of HIV-1 established very early in the course of HIV-1 infection, the maintenance of these immune infection, the maintenance of these immune responses may be critical if the ultimate goal of responses may be critical if the ultimate goal of immune control of HIV-1 is to be achieved. 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 DisadvantagesAdvantages and Disadvantages• Advantages: Advantages:

• Decrease in duration/severity of primary illnessDecrease in duration/severity of primary illness• May lower initial viral load set pointMay lower initial viral load set point• Slows disease progressionSlows disease progression• Enhances recovery of CD4 cell populationsEnhances recovery of CD4 cell populations• Early therapy may reduce rates of viral mutationsEarly therapy may reduce rates of viral mutations• Decreases viral transmission Decreases viral transmission

• 10-20X more infectious in acute stage10-20X more infectious in acute stage• 50% of transmission due to acute hyperinfectiousness50% of transmission due to acute hyperinfectiousness

• Disadvantages:Disadvantages:• Side effects may adversely affect quality of lifeSide effects may adversely affect quality of life• Establishing adherence may be difficult in acute illnessEstablishing adherence may be difficult in acute illness• More ARV exposure More ARV exposure more ARV resistance more ARV resistance

From HIV Webstudy – University of Washington 2006

Who gets ARV’s in Who gets ARV’s in Tanzania? Tanzania?

d4T/3TC/NVP d4T/3TC/NVP (triomune)(triomune)

AZT/3TC/NVPAZT/3TC/NVP d4T/3TC/EFV d4T/3TC/EFV (if (if

Tb/anemia)Tb/anemia)

AZT/3TC/EFV AZT/3TC/EFV (if Tb)(if Tb)

AZT/ddI/Lop-rAZT/ddI/Lop-r ABC/ddI/Lop-rABC/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 HIVRevised WHO clinical staging of HIV

Revised WHO clinical staging of HIVRevised WHO clinical staging of HIV

Long-term Non-Progressors (LTNP’s)Long-term Non-Progressors (LTNP’s)• Only compose 5% of HIV infected ptsOnly compose 5% of HIV infected pts• Characterized by absence of progression from HIV Characterized by absence of progression from HIV

infection to AIDS even in the absence of ART for > infection to AIDS even in the absence of ART for > 10 years10 years

• Have been observed to have more preserved anti-Have been observed to have more preserved anti-HIV CD-4 proliferative responses and higher CD-8 HIV CD-4 proliferative responses and higher CD-8 Cytotoxic responsesCytotoxic responses

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.

Fauci, A. S. et. al. Ann Intern Med 1996;124:654-663

20062006 – >25 antiretrovirals available

AtriplaAtripla – approved July 2006: fixed-dose combination of Efavirenz, Emtricitabine, Tenofovir; i tab PO QD

HAART in 2007HAART in 2007

Recommended ART Regimens in Recommended ART Regimens in TanzaniaTanzania

Reason for OptimismReason for Optimism

Initial Dx (9/6/06)Initial Dx (9/6/06)

CD4+ = 66CD4+ = 66

VL = > 750,000 VL = > 750,000 copies/mLcopies/mL

ID clinic (9/20/06)ID clinic (9/20/06)

CD4+ = 188CD4+ = 188

VL = < 100 VL = < 100 copies/mLcopies/mL

Case Presentation#1Case Presentation#1 A 27 yo previously healthy man presents to casualty A 27 yo previously healthy man presents to casualty

complaining of 2 d of fever, sore throat, and complaining of 2 d of fever, sore throat, and generalized body malaise and you note cervical and generalized body malaise and you note cervical and axillary LAD, mild meningismus and a diffuse axillary LAD, mild meningismus and a diffuse maculopapular rash on PEX. On further history, he maculopapular rash on PEX. On further history, he notes an episode of unprotected intercourse roughly 3 notes an episode of unprotected intercourse roughly 3 wks prior. Acute HIV infection is suspected. Which of wks prior. Acute HIV infection is suspected. Which of

the following is true regarding acute HIV?the following is true regarding acute HIV? A.A. < 5% of acute HIV results in clinical illness< 5% of acute HIV results in clinical illness

B.B. >80% of symptomatic acute HIV presents with aseptic >80% of symptomatic acute HIV presents with aseptic meningitis. meningitis.

C.C. Patients recently infected with HIV typically have viral Patients recently infected with HIV typically have viral loads in excess of 50,000 copies/mL within 4 weeks of loads in excess of 50,000 copies/mL within 4 weeks of infectioninfection

D.D. A negative HIV antibody and a viral load of 2,000 A negative HIV antibody and a viral load of 2,000 copies/mL is consistent with acute HIV infectioncopies/mL is consistent with acute HIV infection

Case Presentation#1Case Presentation#1 A 27 yo previously healthy man presents to casualty A 27 yo previously healthy man presents to casualty

complaining of 2 d of fever, sore throat, and complaining of 2 d of fever, sore throat, and generalized body malaise and you note cervical and generalized body malaise and you note cervical and axillary LAD, mild meningismus and a diffuse axillary LAD, mild meningismus and a diffuse maculopapular rash on PEX. On further history, he maculopapular rash on PEX. On further history, he notes an episode of unprotected intercourse roughly 3 notes an episode of unprotected intercourse roughly 3 wks prior. Acute HIV infection is suspected. Which of wks prior. Acute HIV infection is suspected. Which of

the following is true regarding acute HIV?the following is true regarding acute HIV? A.A. < 5% of acute HIV results in clinical illness< 5% of acute HIV results in clinical illness

B.B. >80% of symptomatic acute HIV presents with aseptic >80% of symptomatic acute HIV presents with aseptic meningitis. meningitis.

C.C. Patients recently infected with HIV typically have Patients recently infected with HIV typically have viral loads in excess of 50,000 copies/mL within 4 viral loads in excess of 50,000 copies/mL within 4 weeks of infectionweeks of infection

D.D. A negative HIV antibody and a viral load of 2,000 copies/mL A negative HIV antibody and a viral load of 2,000 copies/mL is consistent with acute HIV infectionis consistent with acute HIV infection

Acute HIV syndromeAcute HIV syndrome Viremia detectable by RT-PCR within 4-11 Viremia detectable by RT-PCR within 4-11 days days Roughly 40-90% of acute infections have Roughly 40-90% of acute infections have symptomatic phase lasting 1-2 wks within 28 symptomatic phase lasting 1-2 wks within 28 days of initial exposuredays of initial exposure High Viral Loads (>100K) are reached within High Viral Loads (>100K) are reached within 2-3 weeks but fall by 6 months to a ‘set point’ 2-3 weeks but fall by 6 months to a ‘set point’ largely determined by strength of CD8 largely determined by strength of CD8 cytotoxic T-cell response, which may predict cytotoxic T-cell response, which may predict progressionprogression Dx only by RT-PCR as sero-conversion takes Dx only by RT-PCR as sero-conversion takes 1-3 mos1-3 mos Pts are Pts are HIGHLYHIGHLY infectious in acute phase infectious in acute phase making early dx and counseling essential to making early dx and counseling essential to prevent spreadprevent spread Initiating therapy during this period is Initiating therapy during this period is controversial with no established standard of controversial with no established standard of carecare

ReferencesReferences CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm, CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm,

Additional Resources: Additional Resources: http://http://www.hivatis.orgwww.hivatis.org , , http://www.hivinsite.org , http://www.aidsinfo.nih.govhttp://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 ResourcesClinical & Educational Resources UW Case-based HIV learning site: UW Case-based HIV learning site: http://depts.washington.edu/hivaids/http://depts.washington.edu/hivaids/ CDC PEP guidelines: CDC PEP guidelines:

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htmhttp://www.cdc.gov/mmwr/preview/mmwrhtml/rr5409a1.htm Hopkins HIV guide: Hopkins HIV guide: http://www.hopkins-hivguide.orghttp://www.hopkins-hivguide.org// MGH/BWH image database: http://www.idimages.org/MGH/BWH image database: http://www.idimages.org/ Baylor Pediatric AIDS Initiative: Baylor Pediatric AIDS Initiative: http://bayloraids.org/http://bayloraids.org/ Hopkins online lectures ‘Principles of Anti-Retroviral Therapies’: Hopkins online lectures ‘Principles of Anti-Retroviral Therapies’:

http://www.ccghe.jhmi.edu/CCG/distance/HIV_Courses/art.asp#Principlhttp://www.ccghe.jhmi.edu/CCG/distance/HIV_Courses/art.asp#Principleses

IDSA/HIVMA practice guidelines: IDSA/HIVMA practice guidelines: http://www.idsociety.org/HIVMA_Template.cfm?http://www.idsociety.org/HIVMA_Template.cfm?Section=Practice_Guidelines2Section=Practice_Guidelines2

CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm , CDC HIV Slidesets: http://www.cdc.gov/hiv/graphics.htm , http://www.cdc.gov/hiv/topics/surveillance/resources/slides/index.htmhttp://www.cdc.gov/hiv/topics/surveillance/resources/slides/index.htm

Additional Resources: http://www.hivatis.org Additional Resources: http://www.hivatis.org Additional Resources: http://www.hivinsite.orgAdditional Resources: http://www.hivinsite.org Additional Resources: http://www.aidsinfo.nih.govAdditional Resources: http://www.aidsinfo.nih.gov