HIV

Jack A. DeHovitz, MD, MPH

Distinguished Service Professor

Department of Medicine

Director, HIV Center for Women and Children

Initial Reports• June 5, 1981: 5 cases of PCP

in gay men from UCLA (MMWR)

• July 3, 1981: 26 additional cases

• Dec 10, 1981: 3 NEJM papers describe cases

Gottlieb MS NEJM 2001;344:1788-91

Other Early Developments 1• 1982:

– Term “AIDS” coined– First cases in women reported– First transfusion and vertically transmitted cases reported

• 1983:– Isolation of a retrovirus from a patient with AIDS – by Montagnier’s group

• 1984: – Detection of HTLV-III in pts with and at risk for AIDS

(Gallo)

Sepkowitz K NEJM 2001;344:1764-72

Source : National AIDS case surveillance data, CDC

Months after OI diagnosis

0.2

0.4

0.6

0.8

1.0

0

1981-1987

Pro

po

rtio

n s

urv

ivin

g

10 30 40 50 60200

Other Early Developments 2

• 1985:– FDA approves first

commercial HIV antibody test

1987:– AZT = first

antiretroviral approved by FDA

Early Antiretroviral Therapy 1

• 1991-92:– ddI, ddC approved– Sequential monotherapy– Ryan White Care Act passed

• 1993: – Concorde: no difference in clinical endpoints over

3 yrs with early vs. deferred AZT

Early Antiretroviral Therapy 2

• 1994:– ACTG 076: AZT reduces mother-to-child

transmission of HIV

• 1994–95:– era of dual combination therapy

The New Treatment Era• 1995-96:

– HIV viral load testing became available • Clinicians could directly assess the effect of antiretrovirals on viral replication (HIV

RNA)

– First protease inhibitors approved by FDA

The Era of HAART• Paradigm: Aim to achieve durable suppression

of HIV viremia

• Striking reductions in HIV-related morbidity and mortality

• Aggressive treatment guidelines: “Hit hard, Hit early!”

• Mathematical models suggested that 3 years of viral suppression would result in eradication

Percentage of Patient-days on HAART

Deaths per 100 Person-Years

0

5

10

15

20

25

30

35

40

1995 1996 1997 1998 1999 2000 2001

Dea

ths

per

100

per

son

-yea

rs

0

25

50

75

100 Percen

tage o

f patien

t-days o

n A

RT

DEATHS

USE OF ART

Mortality vs. ART utilization

Palella F et al. 8th CROI 2001; abstract 268b.

AIDS Mortality Rates: 1996-2001

1998 - 2000 Realism• HIV eradication is not possible with current therapy

– viral “reservoir” in resting T-memory lymphocytes– viral replication continues in lymph nodes even when

HIV RNA in plasma is <50 copies/mL

• Awareness that HIV is a chronic disease• Recognition of long-term toxicities:

– fat redistribution (lipodystrophy)– metabolic abnormalities (insulin resistance, diabetes,

increased lipids)

• 2000: Durban AIDS conference – momentum builds to bring antiretrovirals to the developing world

2001- 2008• Interest in PI-sparing regimens

– Emergence of NNRTI-based regimens

• Deferred initiation of antiretroviral therapy followed by earlier initiation of therapy.

• Interest in treatment interruption strategies– Ultimately not supported by clinical trials

• Simpler, once daily regimens with fewer pills

• New classes of drugs

• Limited biologic preventive interventions

HIV Epidemiology

• Etiology/Natural History

• Distribution of Disease

• Characteristics of Transmission

• Prevention

• Summary

Etiology/Natural History

HIV/AIDS

The Causative Agent (s)

HIV-1Discovered 1983

Lentivirus (subfamily of retrovirus)

World Wide spread

Evolved from Chimpanzee virus?

12 Subtypes

HIV-2Discovered 1986

Limited to West AfricaEvolved from SIV in sooty

mangabeys?Less efficient transmission

Needs more co-receptors for cell entry

Longer incubation period (14 yrs)

Less pathogenic

Role of Bushmeat

• SIV moved from Chimps and sooty mangabeys to humans

• Evolved into pathogenic HIV

• Exposure to primate blood most likely secondary to bushmeat trade

Butchered chimpanzee in middle of photo

Global distribution of HIV-1 subtypes

High prevalence: C (48%) – southern Africa, AsiaA (23%) – Africa

Medium prevalence: B (16%) – North America, western Europe

Quinn TC. 42nd ICAAC, San Diego 2002, #1191

• Other subtypes have low prevalence• Potential implications for vaccines and treatment

Natural History of HIV Infection

Distribution of Disease

• Worldwide

• US

19July 2008 e

Global estimates for adults and children, 2007

• People living with HIV 33 million [30 – 36 million]

• New HIV infections in 2007 2.7 million [1.6 – 3.9 million]

• Deaths due to AIDS in 2007 2.0 million [1.8 – 2.3 million]

20July 2008 e

Total: 33 million (30 – 36 million)

Western & Central Europe

730 000730 000[580 000 – 1.0 million][580 000 – 1.0 million]

Middle East & North Africa

380 000380 000[280 000 – 510 000][280 000 – 510 000]Sub-Saharan Africa

22.0 million22.0 million[20.5 – 23.6 million][20.5 – 23.6 million]

Eastern Europe & Central Asia

1.5 million 1.5 million [1.1 – 1.9 million][1.1 – 1.9 million]

South & South-East Asia

4.2 million4.2 million[3.5 – 5.3 million][3.5 – 5.3 million]Oceania

74 00074 000[66 000 – 93 000][66 000 – 93 000]

North America1.2 million

[760 000 – 2.0 million]

Latin America1.7 million1.7 million

[1.5 – 2.1 million][1.5 – 2.1 million]

East Asia740 000740 000

[480 000 – 1.1 million][480 000 – 1.1 million]Caribbean230 000

[210 000 – 270 000]

Adults and children estimated to be living with HIV, 2007

21July 2008 e

Over 7400 new HIV infections a day in 2007

• More than 96% are in low and middle income countries

• About 1000 are in children under 15 years of age

• About 6300 are in adults aged 15 years and older of whom:

— almost 50% are among women— about 45% are among young people (15-24)

Steinbrook R. N Engl J Med 2008;359:885-887

Estimated Number of People Living with HIV (Panel A) and HIV Prevalence among People 15 to 49 Years of Age (Panel B), Globally and in Sub-Saharan Africa, 1990-2007

U.S. Department of Health and Human ServicesNational Institutes of Health

National Institute on Drug Abuse

Source of Infections with HIV-1 by RegionSource of Infections with HIV-1 by Region

MTCT

Medical Injections

Blood Transfusions

Marital Sex

Casual Sex

Sex Workers

MSM

IDU

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

Asia Sub-Saharan Africa

Latin America and the Caribbean

Eastern Europe

Cohen, M.S., et al. J.Clin.Invest., Vol 118, 1244-1254, 2008

Categorization of HIV/AIDS Pandemic

I - Low Level epidemic

• HIV Prevalence < 5% in risk groups

II - Concentrated epidemic

• HIV prevalence > 5% in risk groups

III - Generalized epidemic

• HIV Prevalence in Adults > 1 %

AIDS in Africa

70% of all AIDS patients live in Sub-Saharan Africa

66% of patients with tuberculosis in Africa are co-infected with HIV

40% of deaths in Africa are secondary to AIDS

12.1 million African children orphaned

30

35

40

45

50

55

60

65

1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

Impact of HIV on life expectancy in Africa

Low HIV prevalence:MadagascarSenegalMali

High HIV prevalence:ZimbabweSouth AfricaBotswana

Life

exp

ecta

ncy

(yea

rs)

Source: UN Department of Economic and Social Affairs (2001) World Population Prospects, The 2000 Revision

The Worst is Yet to Come: The AIDS Orphans

0

50

100

150

200

250

300

350

400

450

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000

Nu

mb

er o

f H

IV p

osi

tive

cas

es

Estonia Lithuania

Numbers of HIV positive cases in Estonia and Lithuania, 1991 - 2000 (06/2000)*

20

40

60

8019

83

1985

1987

1989

1991

1993

1995

HIV

pre

vale

nce

(%)

Rapid HIV spread among IDUsPrevalence quickly rising to 40% or more

Edinburgh

Bangkok

Myanmar

Manipur & Yunnan

Odessa

Ho Chi Minh City

HIV-1 infection-US

• Almost 1,000,000 infected in US

• Highest rates in MSM, IDUs, and their sexual partners.

• Approximately ¼ not aware of HIV status

• HIV-2 rare

• Approximately 55,000 new infections/yr

Copyright restrictions may apply.

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

Estimated New Human Immunodeficiency Virus (HIV) Infections, Extended Back-Calculation Model, 50 US States and the District of Columbia, 1977-2006

Number of AIDS cases, deaths and persons living with AIDS in the US

Science 305;2004:1243

Public Health Need for Rapid HIV Tests

• High rates of non-return for test results• Need for immediate information or referral for

treatment choices– Perinatal settings– Post-exposure treatment settings

• Screening in high-volume, high-prevalence settings

HIV/AIDS in New York City• 94,495 New Yorkers are known to be living with

HIV or AIDS– 60,807 diagnosed with AIDS (15% of all U.S. cases)– 33,688 diagnosed with HIV (non-AIDS)

• NYC has highest AIDS case rate in U.S.– 3x national average, 60x HP2010 target– More AIDS cases than Los Angeles, San Francisco,

Miami & Washington DC combined

• Estimated 20,000 more are HIV-positive, but do not know their status

Data complete as of 12/31/04

HIV Prevalence in NYC Now 1.5%But Higher in Many Subgroups

0.5% 1.5% 2.5%4.0% 5.0%

8.5%10.0%

12.0%

19.5%

25.0%

0%

10%

20%

30%U

S

NY

C

Afr

ican

Am

eric

ans

Men

livi

ng in

Man

hatta

n

Men

age

40-

49

Bla

ck m

enag

e 40

-49

MS

M

IDU

s

Bla

ck m

enag

e 40

-49

inM

anha

ttan

MS

M in

Che

lsea

% H

IV-P

ositi

ve

Note: Data include estimates of undiagnosed cases, rounded to nearest 0.5%

Transmission of HIV

• Sexual

• Perinatal

• Transfusion

• Occupational

• Injection Drug use

Royce, R. A. et al. N Engl J Med 1997;336:1072-1078

Per-Contact Probability of HIV Transmission

Sexual Transmission of HIV

• Worldwide epidemic driven by sexual transmission

• HIV isolated from semen and vaginal secretions

• Risk of transmission directly related to viral load and acute infections

• Heterosexual transmission occurs more readily from male to female

Cohen et al, JID  2005;191:1391-1393

Perinatal Transmission

• 25% transmission rate in pre AZT era• All children born to HIV infected women are

antibody + at birth• Breast feeding is proscribed in developing nations

after birth• Combination of C-section and ART in women has

reduced transmission to less than 3%• Transmission, if it occurs, typically occurs at

birth.

Incidence of Perinatally-Acquired AIDS United States, 1985-June 2000*

*Reported through December 2000

0

100

200

300

400

500

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00

Half Year of Diagnosis

No.

of

Cas

es

PACTG 076

USPHS ZDV recs

81% decline

Transmission of HIVTransmission of HIV

25%25%

14%14%

40%40%

Occupational HIV Infection

• Occupationally acquired HIV infection among HCW reported through 6/99– 137 possible cases of HIV transmission– 57 documented cases of HIV infection

• Most exposures do not result in infection

• Risk is approximately 1/250

Prevention

• Behavior• Microbicide• Cervical Barriers• Therapy to suppress HSV-2• Male Circumcision• Pre-exposure prophylaxis with ART• Expanded access to therapy• Vaccine

Source: National STD/AIDS Control Programmes, Senegal and Uganda Armed Forces Research Institute of Medical Sciences, Thailand

00

55

1010

1515

2020

2525

3030

89 90 91 92 93 94 95 96 97 98 99

HIV

pre

vale

nc

e (%

)H

IV p

reva

len

ce

(%)

Kampala, <20 year old ANC

Thailand, 21 year old military conscripts

Dakar, all ages ANC

Trends in HIV prevalence in selected populations Trends in HIV prevalence in selected populations in Kampala, Uganda; Dakar, Senegal; and Thailand;in Kampala, Uganda; Dakar, Senegal; and Thailand;

1989 to 19991989 to 1999

Proportion of sex workers and sex workers’ Proportion of sex workers and sex workers’ clients clients

always using condoms with commercialalways using condoms with commercialpartners, Cambodia, 1997 to 1999partners, Cambodia, 1997 to 1999

0

10

20

30

40

50

60

70

80

90

1997 1998 1999

Pro

po

rtio

n r

epo

rtin

g c

on

sist

ent

con

do

m u

se (

%)

brothel-based sex workers

military/police

motorbike taxi drivers

beer promotion women

Source: National AIDS Programme, Cambodia, and Family Health International, 2000

Increasing rates of high-risk behavior and STDs in San Francisco

Predictors of high-risk behavior among HIV+ individuals2

1. Gibson S, et al. XIV Int AIDS Conference, 2002, #3430; 2. Colfax G, et al. ibid, #3445

STDs, high-risk behavior, HIV incidence in MSM1

Unprotected anal sex

Unprotected anal sex, multiple partners

Rectal gonorrhea

Early syphilis

• Belief that undetectable VL reduces transmission vs no change in transmission: AOR 5.9 (95% CI 1.9–19)

• Most recent VL undetectable vs detectable: AOR 9.3 (95% CI 2.3–37)

05

10152025303540

97 98 99 2000 2001

Pe

rce

nt

0

50

100

150

200

250

97 98 99 2000 2001

No

. p

ati

en

ts

Moore, J. P. N Engl J Med 2005;352:298-300

Possible Actions of a Vaginally Administered Topical Microbicide

Severe P et al. N Engl J Med 2005;353:2325-2334

Kaplan-Meier Estimate of the Proportion of Adult and Adolescent Patients Surviving after the Initiation of Antiretroviral Therapy

Kim J and Farmer P. N Engl J Med 2006;355:645-647

Haitian Patient, before and after Receiving Free Treatment for HIV Infection and Tuberculosis

HankinsUNAIDS

Geneva,Dec 5, 2006

Evidence on male circumcision and HIV preventionStrategies and Approaches for Male Circumcision Programming

MALE CIRCUMCISION AND POPULATION BASED HIV PREVALENCE IN AFRICA

0 10 20 30 40

Botswana

Lesotho

Zambia

Tanzania

Kenya

Cameroon

Ghana

Burkina Faso

Guinea

Sierra Leone

Senegal

Sources: ORC/MACRO, 2005, USAID, 2002

High (>80%) male circumcision

Low (<20%) male circumcision

Biological Rationale for HIV linkBiological plausibility

Inner mucosa of foreskin is rich in HIV target cells, ie Langerhans, dendritic, CD4+, macrophages

External foreskin/shaft keratinized and not vulnerable

After circumcision, only vulnerable mucosa is meatus

Foreskin is retracted over shaft during intercourse Large inner mucosal surface exposure Micro-tears, especially of frenulum

Intact foreskin associated with infections Genital ulcer disease Balanitis/phimosis Possible increased HIV entry or shedding

AIDS Vaccine DevelopmentAIDS Vaccine Development

• Rational, empiric approaches to vaccine development have not been successful to date

• Fundamental questions regarding HIV disease and the host response to the virus need to be answered.

• Fresh new ideas beyond the scope of classic vaccinology are urgently needed.

Candidate Vaccines Currently in Clinical Trials

Johnston M, Fauci A. N Engl J Med 2007;356:2073-2081

Potential Scientific Obstacles

• The window of opportunity for the immune system to clear the initial infection is narrow, since HIV integrates and establishes latent infection within days or weeks

• Viral diversity• Animal models• Conserved antibody targets on the outer

envelope protein are "hidden" from immune recognition.

• Destruction of CD4+ T cells begins early after infection.

Logistical and Ethical

Challenges• Behavioral factors in exposure

• Efficacy trials in the U.S.

• Clinical trials in developing countries

• Lack of consensus on ethical issues such as treatment

• Potential social harms to volunteers

Conclusions

• Increasing number of HIV+’s in US as a result of new infections and new therapy.

• Epidemic in developing world continues• Challenge of integrating prevention and

therapy• Prevention efforts in US need to be

maintained and focused on individuals known to be HIV+