acute hiv infection lessons learned and gaps in our knowledge charles hicks, m.d. professor of...

Acute HIV InfectionLessons Learned and Gaps in our

Knowledge

Charles Hicks, M.D.Professor of Medicine

Duke University Medical Center

Durham, North Carolina, USA

Introduction

• There is a growing body of data regarding acute HIV infection – for clinicians, management guidelines were published in 2010 (NY State Dept Health AIDS Institute: www.hivguidelines.org)

• But most recommendations represent expert opinion rather than established research findings

• Basic science and clinical research results form the basis for current studies and treatment management approaches

Things we know….

• HIV infection is most often initiated by a single strain and then disseminates rapidly

• Escape from immune response occurs rapidly and host defenses do not prevent infection

• Virus often (but not always) replicates to a very high level and transmission during early infection is a major risk

A Single R5 Virus from “A SWARM” Infects

Donor(variable)

Mucosa Recipient

Abortive

Less fit or attenuated

Abortive

Abortive

Time (days)0 7 2114 28

Keele et al., PNAS 2008

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

Conclusions

CD4

CCR5Inflammatory cytokines

Genital mucosa

STIsHormonal cyclesBehavioral factors

Blood

Higher concentrations of inflammatory cytokines in the genital tract would recruit more target cells, increasing

viral replication, resulting in more virus being seeded into the systemic compartment and greater CD4 depletion

Roberts L et al. XVIII Intl AIDS Conf 2010; abst 5352

McMichael, Borrow, Tomaras, Goonetilleke, Haynes. Nature Immunology Reviews (2010)

The First Innate, B cell, and T cell Responses to HIV-1 Transmission

Things we think we know….

The clinical expression of AHI is highly variable

(?50% asymptomatic)• As a result, diagnosis of AHI is challenging and

requires a high index of suspicion – many persons with AHI do NOT have a very high viral load

• Treatment is probably worthwhile– Effect on HIV transmission– Benefit to the person with AHI– Impact of transmitted resistance – should treatment be

delayed while awaiting resistance test results?

Duke-UNC HIV CohortMedian Range IQR* N

Age 31 (18-66) (25-39) 43Timeline (days):

Estimated date of infection† to AHI diagnosis 24 (15-62) (19-30) 43Estimate date of infection† to ART start 45 (23-103) (34-53) 43AHI diagnosis to ART start 19 (4-41) (14-25) 43ART initiation to VL<400 copies/mL 55 (0-170) (17-82.5) 40ART initiation to VL<50copies/mL 110 (14-260) (59-168) 37

Viral Loads (copies/mL)Baseline 112,681 (399-14538865) (31402-750000) 43Peak 596,908 (5628-84545454) (112681-2585000) 43Week 16 49 (49-918) (49-99) 35Week 24 49 (49-878) (49-49) 35Week 48 49 (49-54721) (49-49) 25Week 96 49 (49-4678) (49-49) 8

CD4 (cells/mm3)Baseline CD4 (cells/mm3) 521 (13-1012) (304-630) 43Nadir CD4 (cells/mm3) 417 (13-870) (286-587) 43Week 24 590 (143-979) (488-734) 34Week 48 664 (167-965) (510-816) 26Week 96 675 (486-969) (642-768) 6

65.6 (23-95) (52-83) 33Baseline CD8+CD38+HLADR+ (%)

* IQR = interquartile range; †= Infection was estimated as 14 days prior to symptom onset

RESULTS AHI

Clinical immunological and virological features of AHI patients

* Expressed as log10 copies/mL **MN=mononucleosis-like symptoms, R=respiratory, GI=gastrointestinal, P= pharyngitis, S=evidence of sexually transmitted infection (discharge, dysuria) except for ulcer, U=genital ulcer, LTFU=Lost to follow-up

Subject Sex Age

HIV-RNA*

Symptoms** (d7)

CD4cnt CD4:CD8

% Activated

CD8

(d0) (d7) (d7) (d7)

67 F 31 6.09 MN, R, S, P 850 0.30 67.7

101 M 34 ND MN, R, GI, P 239 0.55 59.3

148 M 40 6.88 R, GI, S, P 441 0.40 59.6

188 M 34 5.92 MN, R, P 413 0.36 69.1

197 M 59 6.41 U, P 180 0.10 94.7

221 F 57 6.32 MN, R, GI, S,P 355 0.63 87.8

212 M 30 3.35 LTFU ND ND ND

Median

6.21 384 0.38 68.4

(IQR) (5.92-6.41) (239-441) (0.30-0.55) (59.6-87.8)

Powers K, et al. XVIII Intl AIDS Conf 2010 abst

Diagnosing acute HIV infection requires a high

index of suspicion!!

Number of Visits to Health Care Provider Before Proper Diagnosis of PHI

0

10

20

30

40

50

60

ONE TWO >THREE

Number of Visits

Per

cen

tage

of

Per

son

s

Duke-UNC Acute HIV Cohort

Time to Diagnosis After First Presentation to a Health Care

Provider

0

1

2

3

4

0 10 20 30 40 50 60 70

Days to Diagnosis after First Presentation

Nu

mb

er

of

Pati

en

ts


What testing tools would help with the diagnosis of

acute HIV infection?

Architect HIV Ag-Ab test• The ARCHITECT HIV Ag/Ab Combo assay is a

chemiluminescent microparticle immunoassay (CMIA) for the simultaneous qualitative detection of human immunodeficiency virus (HIV) p24 antigen and antibodies to HIV type 1 (HIV-1 group M and group O) and/or type 2 (HIV-2) in serum and plasma

Better still: a point-of-care rapid test for HIV antigen and HIV antibody

Diagnosing primary HIV infection (PHI)why do we care?

• Individual benefits of diagnosis/treatment of PHI– Lower viral set point– Preserve CD4 cells, especially HIV-specific– Improve quality of immune response– Limit viral diversity– Limit size of latently infected reservoir

• Public Health benefits– Diminish potential spread of HIV to sexual partners– Apply preventive strategies to save health care resources

Sexual Transmission Efficiency in Different HIV Intervals

Source: Galvin/Cohen, 2004

Acute “Early” HIV patients responsible for 8-43% of HIV transmission in serodiscordant couples (Pinkerton, AIDS Behavior, 2008)

38% of new cases due to EHI in Lilongwe

1970 1980 1990 2000 2010 2020 2030 2040 2050 20600

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Year

Prop

ortio

n ne

w c

ases

due

to E

HI Best fitting model estimates

95% credible intervals

38%

19%

58%

Powers K, et al. XVIII Intl AIDS Conf 2010 abst

MTCTn (%) No MTCT Total

AHI 12 (38.7) 19 31

No AHI 35 (1.7) 1986 2021

Total 47 (2.3) 2005 2052

Acute HIV Infection (AHI) During Pregnancy, NY State, 2002-20042

Review of 2052 pregnant women with HIV in NY State 2002-20042

31/2052 (1.5%) had acute HIV infection during pregnancy, accounting for 26% of HIV transmissions

Rate of HIV transmission among women with AHI was 38.7% vs 1.7% among women with established HIV

Results of studies reinforce need for 2nd HIV antibody test in 3rd trimester for women who initially test negative and immediate VL testing for women with symptoms of acute HIV

Acute HIV During Pregnancy and Risk of Maternal-Child

Transmission

Data review, 1999–2001, 10 US States1

4006 Deliveries by HIV-infected women― 58 (1.4%) with documented

seroconversion during pregnancy― Vertical transmission occurred in 17/58

(29.3%) of seroconverters vs 4.8% with chronic HIV

― No data on use of ART

MTCT = mother-to-child transmission.1. Sansom S, et al. 16th IAS; August 12–18, 2006; Toronto, Canada. Abstract WEPE0269; 2. Birkhead G, et al. 16th IAS; August 12–18, 2006; Toronto, Canada. Abstract WEPE0271.

Things that are puzzling….

Gaps in our understanding (clinical and basic science)• Where are the women with AHI?• How long should we continue treatment if ART is started

during acute HIV infection?• What about resistance testing – should we wait for

results before starting treatment?• Basic science gaps in knowledge center around the first

few days near transmission – vaccine issues: – Is the transmitted virus cell-associated or cell-free?– What are the first cells infected? increasing evidence from non-

human primate studies indicate it is CD4+ CCR5-tropic T cells; but work still ongoing to rule out macrophages or other cells

Gender in PHI Cohort

N %Gender

Male 39 91%Female 4 9%

Race

Caucasian 27 63%African American 15 35%Asian 1 2%

MSM 35 81%IVDU 2 5%Ever Alcohol 30 70%Ever Drug Use 24 56%Ever Hard drug Use 9 21%Symptoms 43 100%STD w/in 8 wks prior to Dx 3 7%NNRTI resistance at baseline 1 2%Resistance to initial ART regimen 3 7%

TABLE 1: Baseline Characteristics of AHI Subjects

Total(N = 43)

Grupo Argentino de SeroconversiónGrupo Argentino de Seroconversión

Baseline characteristics (n=134)• Sex: 109 male (81%), 25 female (3 pregnant)• Age, median: 32 years old (IQR 25-39)• Risk: MSM 53 %

Heterosexual 37%

IDU 1%

• HIV-test: Negative WB 9%

Indeterminate WB 40%

Seroconversion 51%

• 28 cases with HIV-positive partner• Median Viral load: 4.87 log copies/ml (IQR 4.11-5.51)• Median CD4: 479 cells/L (IQR 341-682)

Requested by patients in 33%

Serna-Bolea XVIII Intl AIDS Conf 2010; abst 7287

The Case for Earlier Initiation of Therapy

• Easier, more potent, and less toxic therapy

Treatment of Acute HIV Infection

• There are no controlled trials demonstrating clear benefit of HAART for acute HIV infection

• Potential benefits include:– Reduce the size of the viral reservoir– Preserve immune function– Increase the possibility of cure– Health benefits to the individual– Reduce HIV transmission

From: Fauci A. New concepts in HIV/AIDS pathogenesis: implications for interventions. XVIII International AIDS Conference, Vienna.

Treatment responseDuke-UNC acute HIV cohort


Grupo Argentino de SeroconversiónGrupo Argentino de Seroconversión

12-month follow-up

134 PHI patients

Initiated HAART 42

Progressed*3 (7%)

Untreated92

Progressed*: 24 (26%)

- Clinical: 12 (1 death)

- Immunological

: 12

* HIV progression:- Clinical: B or C event, or death.- Immunological: CD4 < 350 cells/l.

p=0.01

Serna-Bolea XVIII Intl AIDS Conf 2010; abst 7287

“Half of what we have taught you is wrong. Unfortunately, we

do not know which half.”

– C. Sidney Burwell, M.D.Address to the graduation class

Harvard Medical School

Acknowledgements• The many patients with AHI who have been brave enough to

participate in research• Colleagues at Duke (Bart Haynes, Georgia Tomaras, Mehri

McKellar, Kara McGee, Guido Ferrari, Kent Weinhold) • UNC – Joe Eron, Myron Cohen, David Margolis, Cindy Gay,

JoAnn Kuruc, Susan Fiscus• Funding from the National Institutes of Health (NIAID,

CHAVI, AIEDRP, CFAR at Duke and UNC)• Assistance from BMS, Gilead Sciences, BI, Tibotec

acute hiv infection lessons learned and gaps in our knowledge charles hicks, m.d. professor of...

Documents

hiv transmissionbenefit

dukeunc hiv cohort

diagnosis of ahi

clinical research results

clinical expression

hiv atmucosal surface

cd4 cells

genital ulcer