Primary HIV Infection and Prevention

Rachel Baden, M.D.

Division of Infectious Diseases

Beth Israel Deaconess Medical Center

Harvard Medical School

Clinical Presentation

• “Sam” presented to clinic

• Unprotected sex with male partner 10 days prior

• Tested negative for HIV 18 months ago

• Flu like illness characterized by rash, fever, oral ulcers, and diffuse lymphadenopathy

Clinical Presentation (cont.)

• HIV antibody negative

• HIV viral load greater than 750,000 copies/mL

• Repeat testing 2 weeks later demonstrated positive antibody and western blot

• CD4 count 464 cells/mm3

• Symptoms resolved after 10 days

Terminology

• Primary HIV Infection (PHI)

– Phase from transmission to seroconversion (SC)

– Highly dynamic state: acute retroviral syndrome

• Early HIV: – Less well-defined; SC through first 6-12 months

– Viral set point correlated with disease progression

Kassutto and Rosenberg, CID 2004Lyles et al, JID 2000

Natural course of HIV infection

Signs and symptoms of Primary HIV

• Fever (80%)• Malaise (68%)• Rash (51%)• Oral Ulcers (37%)*• Weight loss (32)*• Aseptic meningitis• Anorexia• Increased LFT’s

• Arthralgias• Myalgia• Pharyngitis• Night sweats• N/V/D• Headaches• Photophobia

Hecht et al. AIDS, 2002

Daar et al. Ann Int Med, 2001

* Fever/Rash combined, oral ulcers and weight loss most specific

How often do we see Acute HIV?• 0.3% consecutive, unselected ED visits in

Baltimore– Clark, JID 1994

• 1% urgent care clinic patients with “any viral symptoms” at BMC– Pincus, CID 2003

• 1% of MGH patients tested for EBV mononucleosis with a negative heterophile test– Rosenberg, NEJM 1999: If you are thinking mono, “Think

HIV”

How often do we recognize Acute HIV?

• Schacker natural history cohort (1996)– 89% developed symptoms consistent with ARS– 95% symptomatic pts sought care– PCP (48%), ED(31%), UC (21%)– Dx considered in only 26%

• More contemporary cohort (2005)– 20 patients; 85% symptomatic – diagnosis considered in 14%

Schacker, Ann Int Med 1996

Hightow et al, CROI 2005

Routine testing can miss Primary HIV Infection

• North Carolina- 606 cases detected in a 12 month period, 23 were missed by antibody testing alone

• CDC- San Francisco clinic with high risk patients had 116 cases detected, 11 missed by antibody testing alone

Pilcher et al. NEJM, 2005

Patel et al. JAIDS, 2006

Testing for Primary HIV Infection must include both antibody testing and RNA testing (viral load)

“Sam”: Should treatment be started?

Potential Benefits of Treating Acute Infection:-Beneficial effect on laboratory markers of disease progression -Decrease viral setpoint and thereby decrease rate of disease progression-May mitigate loss of gastrointestinal lymphoid tissue -Can decrease rate of transmission

Drawbacks to Treating Acute HIV Infection:-No proven clinical benefit-Drug toxicities-Development of drug resistance-Adverse effect on quality of life

From the DHHS guidelines…..

Potential Benefits of Treating Acute Infection:-Beneficial effect on laboratory markers of disease progression -Decrease viral setpoint and thereby decrease rate of disease progression-May mitigate loss of gastrointestinal lymphoid tissue -Can decrease rate of transmission

Drawbacks to Treating Acute HIV Infection:-No proven clinical benefit-Drug toxicities-Development of drug resistance-Adverse effect on quality of life

From the DHHS guidelines…..

Impact of treatment during PHI on the immune response

• Preservation of HIV-specific CD4+ responses compared to chronic infected

• Breadth of CD4+ response increased with treatment

• Treatment allows maturation of CD8+ T cell responses- thought to be important in control of replication

Rosenberg et al, Nature 2000 Altfeld et al, J Exp Med, 2001

Champagne et al, Nature 2001 Hicks et al, J Exp Immunol, 2007

Rosenberg et al, Nature 2000

Preservation of HIV-specific CD4+ responses

• 16 HIV+ individuals diagnosed at time of seroconversion

• Immediate ART• 35 HIV- controls;

12 chronic infection, 9 LTNP

• CD4 responses to gag Ag by Lymphocyte Proliferation Assay

Poor decline in VL;Resistant virus

Comparison of mean CD4+ T lymphocyte countsover time in treated vs untreated acute/early HIV-1 infection

baseline 6 12 24 360

100

200

300

400

500

600

700

800Treated cohortMACS

CD

4+ T

lym

ph

ocy

te c

ou

nt

(cel

ls/m

m3)

P=0.01 P=0.001 P=0.0007

Time (months)

Kassutto et al, CID 2006

Potential Benefits of Treating Acute Infection:-Beneficial effect on laboratory markers of disease progression -Decrease viral setpoint and thereby decrease rate of disease progression-May mitigate loss of gastrointestinal lymphoid tissue -Can decrease rate of transmission

Drawbacks toTreating Acute HIV Infection:-No proven clinical benefit-Drug toxicities-Development of drug resistance-Adverse effect on quality of life

From the DHHS guidelines…..

HIV

Vir

al L

oad

1 year

Rapid Progression

Slow Progression

Mellors et al, Annals 1997

Goal of early therapy- delay progression

Natural history (MACS cohort)

Early treatment may change the viral set point and preserve immune function-shift patient to lower curve

ACTG 5217• 130 (of 150) Subjects with early infection (<6 mo)• Randomized to treatment (TDF/FTC/Kaletra) x 9 mo vs no

treatment• Study stopped by DSMB because of more rapid disease

progression (requiring ART) in the no treatment arm by 72 wks (34% vs 6%)

• Inadequate virologic data to make conclusions about set point

• “Limited ART during early HIV-1 infection modestly delayed the need for subsequent initiation of ART”

Hogan et al, CROI 2010

Potential Benefits of Treating Acute Infection:-Beneficial effect on laboratory markers of disease progression -Decrease viral setpoint and thereby decrease rate of disease progression -May mitigate loss of gastrointestinal lymphoid tissue -Can decrease rate of transmission

Drawbacks toTreating Acute HIV Infection:-No proven clinical benefit-Drug toxicities-Development of drug resistance-Adverse effect on quality of life

From the DHHS guidelines…..

Gut Immunity and Acute Infection

• CD4+ T lymphocyte depletion in the gut– Happens very early – Likely a critical event in HIV pathogenesis

• Effect of early ART?– SIV models: early treatment may allow CD4 T

lymphocyte restoration

Verhoeven, J Virol 2008

Gut Immunity and Acute Infection

• 13 patients studied with primary infection

• No significant difference in peripheral CD4 counts between HIV+/HIV-

• Significant CD4+ T cell depletion in GI mucosal cells

• 8 patients started HAART during PHI-all undetectable VL in plasma- no significant GI tract immune reconstitution

Mehandru et al, J Exp Med 2004

Potential Benefits of Treating Acute Infection:-Beneficial effect on laboratory markers of disease progression -Decrease viral setpoint and thereby decrease rate of disease progression. -May mitigate loss of gastrointestinal lymphoid tissue -Can decrease rate of transmission

Drawbacks toTreating Acute HIV Infection:-No proven clinical benefit-Drug toxicities-Development of drug resistance-Adverse effect on quality of life.

From the DHHS guidelines…..

The epidemiology of transmission

Wawer et al, JID 2005Brenner et al, JID 2007

Transmission is 10-12x higherin early infection

Quebec study: Early infection accounts for approximately 50% of new transmissions

HIV diagnosis in patients with recent infection may impact behavior

• HIVNET vaccine preparedness study – Large proportion reported high risk behavior

prior to diagnosis that may have unknowingly resulted in secondary transmission

– Risky behavior declined significantly after diagnosis but gradual increased risky behavior at 1 year post diagnosis

• Recently Infected MSM– ½ of patients had fewer sexual partners in the 3

months after diagnosis Colfax et al, AIDS 2002

Gorbach et al, JAIDS 2006

Awareness of Serostatus Among People With HIV and Estimates of Transmission

~25% Unaware of

infection

~75% Aware of infection

People Living with HIV/AIDS: 1,039,000–1,185,000

New Sexual Infections Each Year: ~32,000

Accounting for: ~54% of new

infections

~46% of new

infections

Marks et al. AIDS. 2006;20:1447-1450.

Community Viral Load Mirrors Reduced Rate of New HIV Cases in San Francisco

• Retrospective analysis of relationship between community viral load (mean of summed individual HIV-1 RNA results per yr) and new HIV diagnoses

Das-Douglas M, et al. CROI 2010. Abstract 33.

Mean CVL

0

5000

10,000

15,000

20,000

25,000

30,000

2004 2005 2006 2007 2008Yr

Mea

n C

omm

un

ity

Vir

al L

oad

(c

opie

s/m

L)

*Data insufficient to prove significant association with reduced HIV incidence.

Newly diagnosed and reported HIV cases

0

200

400

600

800

1000

1200 Nu

mb

er of New

ly Diagn

osed

HIV

Cases

P = .005 for association*

798

642523 518

434

• Period of declining new HIV diagnoses in BC coincident with increased HIV testing rates, increased uptake of antiretroviral therapy, and decrease in community viral load (1996-2008)

– Decline in new HIV diagnoses despite increases in syphilis, gonorrhea, chlamydia

Montaner J, et al. CROI 2010. Abstract 88LB..19

9620

0920

0820

0720

0620

0520

0420

0320

0220

0120

0019

9919

9819

97

≥ 50,000

10,000-49,999

3500-9999

500-3499

< 500

Reduction in New HIV Diagnoses in BC: Testing, HAART, and

Community VL

0

2000

4000

6000

8000

10,000

12,000

Censored at the time of death or move

Pat

ien

ts (

n)

HIV-1 RNA, copies/mL

0

200

400

600

New HIV+diagnoses (all)

New

HIV

+ D

iagnoses (n

)

800

1000

1200

1400

Which ARVs should be used to treat acute HIV infection?

3 drug regimen: Tenofovir/FTC +AZT or Darunavir/Ritvs

5 drug regimen:Tenofovir/FTC/ PI +Maroviroc/Raltegravir

No difference was found in response rates, plasma viral loads or immune reconstitution between the two regimens.

Studies on GI tract and other reservoirs still pendingMarkowitz et al. CROI 2011

Back to our patient “Sam”

• He was interested in the possibility of treatment

• Referred him to the MGH for their primary HIV study

• He was enrolled in one of their treatment arms and is currently doing well on treatment, with a suppressed VL and CD4 count of 708 copies/ml

A PHASE I CLINICAL TRIAL TO EVALUATE THE INITIATION OF

TREATMENT VERSUS NO TREATMENT DURING ACUTE HIV-1 INFECTION

A Single Center Trial of the Partners AIDS Research Center and the Division of Infectious Disease

at Massachusetts General Hospital

617-724-0070

Agents on the horizon and their role in acute HIV??• Attachment Inhibitors-bind viral envelope

glycoprotein gp120 and interfere with the attachment of the virus to CD4 receptor

• Entry inhibitors targeting gp 41

• Newer generation integrase inhibitors

Thank you

• Chris Rowley, M.D.

• Sigall Bell, M.D.

• Michael Wong, M.D.