HIV History and Future - Kathleen Squires MD

HIV at 30:

History and Future Kathleen E. Squires, M.D.

Professor of Medicine

Director, Division of Infectious Diseases

Thomas Jefferson University and Hospital

Presented at the 41st Annual Symposium

“Global Movement of Infectious Pathogens and Improved Laboratory Detection”

Eastern PA Branch-American Society for Microbiology

November 17, 2011

Thomas Jefferson University, Philadelphia

HIV/AIDS: The Beginning

Initial Cases

• Young previously healthy males

• Presenting with rarely encountered conditions

– Pneumocystis carinii pneumonia

– Kaposi‟s sarcoma

• Rapidly progressive disease and death

• Common risk factor-MSM

Global Summary:

People Living With HIV

North America 1,400,000

Caribbean 240,000

Latin America 2,000,000

North Africa & Middle East

310,000

Sub-Saharan Africa

22,400,000

Western Europe 850,000

East Asia & Pacific 850,000

South & South East Asia 3,800,000

Australia & New Zealand

59,000

Eastern Europe & Central Asia

1,500,000

47% of Cases are Women

6% of Cases are Children Most via Mother-to-Child Transmission

UNAIDS 2010.

CDC Revises Estimation of

New Cases of HIV Infection

Methodology

New non-AIDS HIV cases from 22 states

Use of BED assay to identify recent infections

Stratified extrapolation approach confirmed with back calculation

Revised estimate 2006

56,300 (95% CI: 48,200 - 64,500)

Black

45%

White

35%

Hispanic

17%

Racial

Distribution

Hall HI, et al. JAMA 2008;300:520-529.

Risk Groups 80000

70000

60000

50000

40000

30000

20000

10000

0

Infe

cti

on

s

1977-

1979

1980-

1981

1982-

1983

1984-

1985

1986-

1987

1988-

1990

1991-

1993

1994-

1996

1997-

1999

2000-

2002

2003-

2006

Period

MSM IDU MSM/IDU Heterosexual

A simplified lineage scheme of retroviruses. This phylogenetic tree is not intended to quantitatively

represent evolutionary distances between viruses but to illustrate the relative relatedness between these infectious

agents. As can be seen, there is a greater sequence homology between HIV-1 and SIVcpz, and between HIV-2 and

SIVsm/mac, than there is between the two human pathogens HIV-1 and HIV-2. Also of note in this phylogenetic tree

is the obvious parallel between infection of human and non-human primates. For each class of human pathogen

represented, there is a closely related simian retrovirus.

Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48

Origin of HIV: Lentivirus Family

Tebit, DN, Arts, EJ et al. The Lancet 2011:11;46-48

Worldwide Spread of HIV-1

Kahn JO, Walker BD. N Engl J

Med. 1998;339:33-39.

Exposure to HIV at

mucosal 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

The Pathogenesis of HIV-1 Infection: Compartments

Colon, Duodenum and

Rectum Chromaffin Cells

Lymphocytes in Blood,

Semen and Vaginal Fluid

Skin Langerhans‟ Cells

Bone Marrow

Brain Macrophages

and Glial Cells

Lymph Nodes

Thymus Gland

Lung Alveolar

Macrophages

Gut is area of massive T cell loss

CD4 Cell Count

Natural History of Untreated HIV-1 Infection

Time in Years Infection

CD4

Cells

1000

800

600

400

200

0

Early Opportunistic Infections

Late Opportunistic Infections

+

1 2 3 4 5 6 7 8 9 10 11 12 13 14

HIV Replication Cycle and Sites of Drug Activity

Capsid

proteins

and viral

RNA

CD4

Receptor

Viral RNA

New HIV

particles Protease Reverse

Transcriptase

Unintegrated

double stranded

Viral DNA

Integrated

viral DNA

Viral

mRNA

Integrase

gag-pol

polyprotein

Attachment

and Fusion Uncoating Reverse

Transcription

Integration Transcription Translation

1 2 3 4 5 6 Assembly

And Release

Protease Inhibitors

NRTIs

NNRTIs

Cellular DNA

CCR5 or

CXCR4 co-receptor

HIV Virions

Fusion Inhibitors

Adapted:Levy JA. HIV and the Pathogenesis of AIDS. 2nd ed. Washington, DC: American Society for Microbiology; 1998:9-11

.

Nucleus

Integrase Inhibitors

FDA-Approved Drugs for HIV Therapy:

2011

NNRTIs

Delavirdine (DLV)

Efavirenz (EFV)

Nevirapine (NVP)

Rilpivirine (RLP)

PIs

Amprenavir (APV)

Atazanavir (ATV)

Darunavir (DRV)

Fosamprenavir (FPV)

Indinavir (IDV)

Lopinavir/ritonavir (LPV/RTV)

Nelfinavir (NFV)

Ritonavir (RTV)

Saquinavir (SQV hgc)

Tipranavir (TPV)

Abacavir (ABC)

Didanosine (ddI)

Emtricitabine (FTC)

Lamivudine (3TC)

Stavudine (d4T)

Tenofovir (TDF)

Zalcitabine (ddC)

Zidovudine (ZDV)

3TC/ABC

3TC/ABC/ZDV

3TC/ZDV

FTC/TDF

NRTIs

Fusion Inhibitors (FIs)

Enfuvirtide (ENF)

FDA-Approved Drugs for HIV Therapy:

2011

Multiple Class

EFV/FTC/TDF

RLP/FTC/TDF

Integrase Inhibitors

Maraviroc (MRV)

CCR5 Inhibitors

Raltegravir (RAL)

When to Begin HIV Treatment

DHHS Guidelines < 12/1/2009

HIV Infection

Asymptomatic

Treat

Treat

CD4+ T cells/mm3

Consider

Treatment

DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available

at: http://aidsinfo.nih.gov.

History of AIDS-

defining illness or

severe symptoms

RISKS BENEFITS

<350 >350 Nov 2008

When to Begin Treatment

DHHS Guidelines >12/1/09

HIV Infection

Asymptomatic

Treat

Treat

CD4+ T cells/mm3

Consider

Treatment

DHHS. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents; Available

at: http://aidsinfo.nih.gov.

h/o AIDS-defining

illness , severe sx,

pregnancy, HepB,

HIVAN

50% of

panel say

treat

50% of panel

say optional

<500 >500 Dec 1, 2009

Acute OIs

What Antiretroviral Agents To Start

DHHS guidelines 2011

Preferred regimens

Efavirenz + tenofovir + emtricitabine (Atripla®)

Raltegravir + tenofovir + emtricitabine

Ritonavir-atazanavir + tenofovir + emtricitabine

Ritonavir-darunavir + tenofovir + emtricitabine

Alternative regimens: NNRTIs (NVP or EFV) or other PIs (FPV/r, LPV/r, SQV/r) PLUS

ABC/3TC* or AZT/3TC or TFV/FTC

Acceptable or may be acceptable regimens: EFV+ ddI + (3TC or FTC); Unboosted

ATV with (ABC or AZT)/3TC; Maraviroc + AZT/3TC or Raltegravir + (ABC or AZT)/3TC or

(DRV/r or SQV/r) + (ABC or AZT)/3TC

*Other major combination NRTI agent of ABC/3TC demoted to alternative Dec „09

100

0

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12

400

300

200

Monotherapy

Dual-NRTI combinations

HAART

0

– 1

– 2

– 3

Slide courtesy of C. J. Cohen, MD. Years

Ch

an

ge

in

CD

4+

Ce

ll C

ou

nt

Fro

m B

as

eli

ne

(ce

lls

/mm

3)

Ch

an

ge

in H

IV-1

RN

A F

rom

Ba

se

line

(log

10 c

op

ies

/mL

)

Improving Outcomes With Evolving

Antiretroviral Regimens

CD4+ RNA Monotherapy

Dual-NRTI combinations

HAART

CD4+ RNA

100

0

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06

400

300

200

Monotherapy

Dual-NRTI combinations

HAART

0

– 1

– 2

– 3

Slide courtesy of C. J. Cohen, MD. Years

Ch

an

ge

in

CD

4+

Ce

ll C

ou

nt

Fro

m B

as

eli

ne

(ce

lls

/mm

3)

Ch

an

ge

in H

IV-1

RN

A F

rom

Ba

se

line

(log

10 c

op

ies

/mL

)

Improving Outcomes With Evolving

Antiretroviral Regimens

CD4+ RNA Monotherapy

CD4+ RNA

100

0

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06

400

300

200

Monotherapy

Dual-NRTI combinations

HAART

0

– 1

– 2

– 3

Slide courtesy of C. J. Cohen, MD. Years

Ch

an

ge

in

CD

4+

Ce

ll C

ou

nt

Fro

m B

as

eli

ne

(ce

lls

/mm

3)

Ch

an

ge

in H

IV-1

RN

A F

rom

Ba

se

line

(log

10 c

op

ies

/mL

)

Improving Outcomes With Evolving

Antiretroviral Regimens

CD4+ RNA Monotherapy

Dual-NRTI combinations

CD4+ RNA

100

0

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 02 04 06 08 10 12

400

300

200

Monotherapy

Dual-NRTI combinations

HAART

0

– 1

– 2

– 3

Slide courtesy of C. J. Cohen, MD. Years

Ch

an

ge

in

CD

4+

Ce

ll C

ou

nt

Fro

m B

as

eli

ne

(ce

lls

/mm

3)

Ch

an

ge

in H

IV-1

RN

A F

rom

Ba

se

line

(log

10 c

op

ies

/mL

)

Improving Outcomes With Evolving

Antiretroviral Regimens

CD4+ RNA Monotherapy

Dual-NRTI combinations

HAART

CD4+ RNA

Role of Assays in HIV Management

• HIV resistance assays

– Genotype

– Phenotype

– Virtual Phenotype

• Tropism assays

– Trophile

– Genotype

HIV: The Future

• Chronic Infection

– High rates of virologic suppression in patients on therapy

– ? Nearly normal life span

• Persistent elevated levels of inflammatory markers

• Higher risk of specific co-morbidities

– Cardiac disease, hepatitis B &C/cirrhosis/hepatocellular carcinoma,

non-AIDS associated neoplasm

• Is there a cure?

– NIAID RFA

• 5 funded program project grants

~42-59% chronically

~1,100,000

~21%

People Living

with HIV/AIDS

People with HIV/AIDS

Not In Care

People with HIV Who Don't Know

They Are Infected

~56,000

New Infections, 2006

US HIV Epidemic—For Context

NOTE: Data are estimates. SOURCE: Hall HI, et al., "Estimation of HIV Incidence in the United States". JAMA, Vol. 300, No. 5, August 2008; CDC, MMWR, Vol. 57, No. 39, 2008; Fleming P, et al., "HIV Prevalence in the United States 2000", 9th Conference on Retroviruses and Opportunistic Infections, 2002.

Slide 26

National HIV/AIDS Strategy

http://www.whitehouse.gov/sites/default/files/microsites/ONAP_rpt.pdf

Slide 27

HIV Prevention

• Vaccine-the Holy Grail

• Circumcision

• Pre-exposure prophylaxis

• Treatment as prevention

• Bio-medical prevention

• Can we treat our way out of this epidemic?

• Community viral load

Efficacy of HIV Prevention Strategies

From Randomized Clinical Trials

Abdool Karim SS, et al. Lancet. 2011;[Epub ahead of print].

100 0 20 40 60 80

Efficacy (%)

Study Effect Size, % (95% CI)

ART for prevention; HPTN 052, Africa, Asia, Americas

PrEP for discordant couples; Partners PrEP, Uganda, Kenya

PrEP for heterosexual men and women; TDF2, Botswana

Medical male circumcision; Orange Farm, Rakai, Kisumu

PrEP for MSMs; iPrEX, Americas, Thailand, South Africa

Sexually transmitted diseases treatment; Mwanza, Tanzania

Microbicide; CAPRISA 004, South Africa

HIV vaccine; RV144, Thailand

96 (73-99)

73 (49-85)

63 (21-84)

54 (38-66)

44 (15-63)

42 (21-58)

39 (6-60)

31 (1-51)

Current CDC Guidance on PrEP

http://www.cdc.gov/nchhstp/newsroom/PrEPMSMGuidanceGraphic.html

HPTN 052: Immediate vs Delayed ART in

Serodiscordant Couples

Cohen MS, et al. IAS 2011. Abstract MOAX0102.

Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

Immediate ART

Initiate ART at CD4+ cell count 350-550 cells/mm3

(n = 886 couples)

Delayed ART

Initiate ART at CD4+ cell count ≤ 250 cells/mm3*

(n = 877 couples)

HIV-infected, sexually active

serodiscordant

couples; CD4+ cell count

of the infected partner:

350-550 cells/mm3

(N = 1763 couples)

*Based on 2 consecutive values ≤ 250 cells/mm3.

• Primary efficacy endpoint: virologically linked HIV transmission

• Primary clinical endpoints: WHO stage 4 events, pulmonary TB, severe bacterial

infection and/or death

• Couples received intensive counseling on risk reduction and use of condoms

DSMB recommended release of results as soon as possible following April 28, 2011, review; follow-up

continues but all HIV-infected partners offered ART after release of results

HPTN 052: HIV Transmission Reduced by

96% in Serodiscordant Couples

Single transmission in patient in

immediate ART arm believed

to have occurred close to time therapy

began and prior to HIV-1 RNA

suppression

Total HIV-1 Transmission Events: 39

(4 in immediate arm and

35 in delayed arm; P < .0001)

Linked Transmissions:

28

Unlinked or TBD

Transmissions: 11

P < .001

Immediate

Arm: 1

Delayed Arm:

27

Cohen MS, et al. IAS 2011. Abstract MOAX0102.

Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

HPTN 052: Multivariate Analysis of

Factors Associated With Linked

Transmissions Variable HR 95% CI

Treatment, immediate vs delayed 0.04 0.01-0.28

Baseline CD4+ count, per 100 cells/mm3 decrease 1.24 1.00-1.54

Baseline HIV-1 RNA, per 1 log10 copies/mL increase 2.85 1.51-5.41

Baseline condom use, 100% vs < 100% 0.33 0.12-0.91

Sex of infected partner, male vs female 0.73 0.33-1.65

Cohen MS, et al. IAS 2011. Abstract MOAX0102.

Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

61% of transmissions occurred from infected patient with CD4+ cell count > 350 cells/mm3

All transmissions occurred prior to starting ART

82% of transmissions occurred in African patients

HPTN 052: Primary Clinical Events During

Follow-up • 41% reduction in HIV-related clinical events in HIV-infected patients

randomized to immediate vs delayed therapy

– Excess events in delayed arm driven mainly by TB (33 vs 17 cases),

particularly extrapulmonary TB (17 vs 3 cases)

Fa

ilu

re P

rob

ab

ilit

y

0

0.10

0.15

0.20

0.25

Yrs Since Randomization

0 1 2 3 4 5

0.05

HR: 0.6 (95% CI: 0.4-0.9; P = .01)

Delayed (n = 65)

Immediate (n = 40)

877 886

701 700

317 333

86 85

32 36

25 29

Number at risk

Grinsztejn B, et al. IAS 2011. Abstract MOAX0105.

Cohen MS, et al. N Engl J Med. 2011;[Epub ahead of print].

HIV: The Future

• Can incidence be decreased?

– Routine HIV testing

• CDC 2006 guidance-every person 13-64 should be tested at least

once and undergo repeat testing based on ongoing risk factors

• Emphasis on point-of-care testing

– Aligned with National AIDS Strategy to identify HIV-positive

individuals and facilitate entry to care

– Rapid HIV testing, STI test and treat, ? CD4 cell counts and HIV viral

load

• Use of 4th generation Ag/Ab tests to identify individuals with acute

infection

HIV: The Future

• Can incidence be decreased?

– Access to and retention in care

• Treatment for personal health

• Treatment as prevention (HPTN 052)

• Tension between “mainstreaming” HIV care

and evidence that HIV expert care improves

outcomes

HIV at 50

• Point of care HIV testing

– as routine as RPR

• ART for all diagnosed patients

• Point of care CD4 and HIV VL

– Primary care venues

• ??? Functional cure

• ??? Preventive vaccine