The HIV Pandemic 2008Where Do We Go From Here?

Myron S. Cohen, MD

J. Herbert Bate Professor

Medicine, Microbiology, Public Health

Director, UNC Institute of Global Health

The University of North Carolina-CH

Critical Issues in HIV

• The Pandemic

• Global Treatment

• Prevention

…and UNCs role

The beginning …

Hubei Medical College, 1979

Me

A global view of HIV infectionA global view of HIV infection38.6 million people [33.4‒46.0 million] living with HIV, 2005

2.4

Where is HIV Going Next?

• HIV is STAYING in Africa

• India

• China

• Russia

• ????

About 14,000 new HIV infections dailyAbout 14,000 new HIV infections daily

• >95%95% new infections in developing countries.

• 2,0002,000 in children under 15 years of age.

• 12,00012,000 are in people aged 15-49 years

* about 50% are 15–24 year olds.

* almost 50% are in women

4 new people infected for every person treated!

Epidemic Spread of Disease

Ro = bDC

When Ro >1 epidemic is sustained

b = Efficiency of transmission (…a biological event)

D = Duration of infectiousness

C = Number of people (partners) exposed

Transmission of Infectious Diseases:Biological Requirements

Infectious SusceptibilityInoculum (concentration)Hereditary resistance

Phenotypic factors Innate resistance

Acquired (immune)

resistance

*communicability and virulence are two different concepts

Routes of Exposure and H.I.V. INFECTION ROUTE RISK OF INFECTION

Sexual Transmissiona. Female-to-male transmission………..1 in 700 to 1 in 3,000b. Male-to-female transmission……...….1 in 200 to 1 in 2,000c. Male-to-male transmission………...….1 in 10 to 1 in 1,600d. Fellatio??…………………………….. 0 (CDC) or 6% (SF)

Parenteral transmissiona. Transfusion of infected blood………….95 in 100b. Needle sharing………………………….1 in 150c. Needle stick…………………………..…1 in 200d. Needle stick /AZT PEP…………………1 in 10,000

Transmission from mother to infanta. Without AZT treatment………...…….1 in 4b. With AZT treatment………………….Less than 1 in 10

Royce, Sena, Cates and Cohen, NEJM 336:1072-1078, 1997

Coital Frequency per Month by Age

10.02

8.98 9.11

7.44

15-24 25-29 30-34 35-59

Age

4

5

6

7

8

9

10

11

Co

ital

fre

qu

ency

per

Mo

nth

Hypothesis

1) Estimated transmission rates are too low to explain the epidemic

2) HIV transmission is intermittently AMPLIFIED by increased genital tract shedding3) AMPLIFIED transmission is critical to the

spread of HIV 4) OTHER Sexually Transmitted diseases play

a key role

Biological Determinants That Affect HIV Sexual Transmission

InfectiousnessLevel of Blood Viral Load

Genital Viral Load

Stage of Infection

Genital ulcerations

Inflammatory STDs

Cervical ectopy

Viral Subtype

X4/R5 Phenotype

Hormonal contraception

AcquisitionGenital ulcers

Inflammatory STDs

Cervical ectopy

HLA Haplotype

Chemokines/Cytokines

Hormonal contraception

Lack of Circumcision

HIV

RN

A in

Sem

enH

IV R

NA

in S

emen

(Log

(Log

1010

copi

es/m

l) c

opie

s/m

l)

Acute Infection

Acute Infection

3 wks3 wks Asymptomatic

Asymptomatic

InfectionInfection

HIV Progression

HIV ProgressionAIDSAIDS

00

22

44

66

1/1000 - 1/1000 - 1/10,0001/10,000

1/500 - 1/500 - 1/20001/2000

1/100-1/100-1/10001/1000

Risk of TransmissionRisk of TransmissionReflects Reflects Genital Genital Viral Burden Viral Burden

1/30-1/30-1/701/70

Big Idea I: Transmission in Clusters

HIV

RN

A in

Sem

enH

IV R

NA

in S

emen

(Log

(Log

1010

copi

es/m

l) c

opie

s/m

l)

Acute HIV Infection

Acute HIV Infection

& STD Coinfection

& STD Coinfection

STD Episode

STD Episode

STD Episode

STD EpisodeAIDSAIDS

22

33

44

55

Big Idea II: “Classical” STDs Drive HIV

1/30 or greater odds of transmission 1/30 or greater odds of transmission to a susceptible partner per coital actto a susceptible partner per coital act

Differential Diagnosisof Genital Ulcer Disease

"The Tip of the Iceberg"

90.8%Unrecognized and asymptomatic infection

9.2%Recognized infection

Iceberg represents all those withHSV-2 antibody

UNC Global Health Research Sites“TO BE AND NOT TO SEEM”

Malawi Overview

• Population 10 million• 90% rural• Per Capita income $190

AIDS impact• 900,000 people living with

HIV• 15% adult prevalence• STD Clinic: 47% prevalence

HIV-1 Viremia and SheddingPilcher et al. AIDS, 2007

wk4 wk8 wk16

Established HIV Infection

CD4<350

1

3

5

7

9

CD4>350

Acute HIV Infection

log

10H

IV-1

RN

A c

opie

s p

er m

L

01 July 2002 slide number SSA-7

Number of people who died from HIV/AIDS in sub-Saharan Africa, 1980-2001

0

500

1,000

1,500

2,000

2,500

1980 1983 1986 1989 1992 1995 1998 2001

Thousan

ds

Source: UNAIDS, 2002

Projected life expectancy in African countries with high HIV prevalence, 1995–2000

Source: United Nations Population Division

1955 1960 1965 1970 1975 1980 1985 1990 1995 2000

Average life expectancy at birth, in years65

60

55

50

45

40

35

ZimbabweZimbabwe

ZambiZambiaaUgandaUganda

BotswanaBotswana

MalawiMalawi

In 9 Sub-Saharan African countries, one-fifth to one-third of all children under the age of 15

Were orphaned by the year 2000 34.3

27.4 26.9 27.425.5

23.421.7 20.9 20.3

0

5

10

15

20

25

30

35

Zambia

Malawi

Rwanda

Zimbabwe

Uganda

Botswana

Tanzania

Burkina Faso

Central African Rep.

US Census Bureau

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. 2001; 8th CROI. Abstract 268b.

AIDS Mortality Rates: 1996-2001

ART Access June 2006Geographical region Number of

people receiving ARV

therapy

Estimated need

Coverage

Sub-Saharan Africa 1 040 000 4 600 000 23%

Latin America and the Caribbean

345 000 460 000 75%

East, South and South-East Asia

235 000 1 440 000 16%

Europe and Central Asia

24 000 190 000 13%

North Africa and the Middle East

4 000 75 000 5%

Total 1 650 000 6 800 000 24%

UNAIDS, 2006

Presidential Emergency Plan for AIDS Relief (PEPFAR)

• 15 “focus” countries…(but funds in > 120)• Trained lab personnel, counselors,

infrastructure, distribution/management of ART and other drugs

• Care provided to 3,000,000 people• >600,000 provided ART • $15,000,000,000 over 5 years (maybe more!) ….and The Global Program, Three x Five and

others! As of 2007…THE US IS PRIVIDING 1/3 of ALL

PLANETARY HIV TREATMENT AND CARE

Opportunities to Prevent HIV

1) BEFFORE EXPOSURE

2) AT EXPOSURE (PrEP)

3) AFTER EXPOSURE (PEP)

4) SECONDARY TRANSMISSION

“positive prevention”

Prevention of HIV

1. STD control, behavior change, condom2. Topical microbicides (Trials ongoing)3. The diaphragm (Trial completed!)4. Male circumcision (Trials completed!)5. Antiviral therapy (Trials ongoing) - for HIV (treat both HIV+ or HIV-) - for HSV to prevent HIV (treat HIV+ or-) 2. Societal (Structural) Change: Incentives for

safer sex, needle exchange?

Vaccines for Prevention of HIV Infection

Good News:HIV proteins are immunogenicAnimal success stories with clues to immunity

Bad News:No reliable surrogates of immunity

Short-lived immunity VAXGEN Failure Merck 502,503 Failure (Sept 22,2007)!!!

The Cost : Benefit ratio-Disinhibition

Potential end-points of HIV-vaccine efficacy trials

UNAIDS–97100 1 August 1998

“normal” infectionwith variable levels

of viral load

no protection

no infection

protection against HIVsterilizing immunity

protection against disease (modification of the course of HIV infection in vaccine recipients)

initial infection“controlled”

establishment of chronic infection with low viral load

Merck 502

• AD5, HIV CTL stimulation, no envelope

• Study stopped in September 2007 for FUTILITY!!

• No protection from HIV acquisition

• No reduction in viral load set point

WHATS NEXT?????

This CHAVI web site is at http://www.chavi.org

Relationship Between HIV and Male Circumcision

0

5

10

15

20

25

0 20 40 60 80 100

% Circumcised males

HIV

Ser

op

reva

len

ce (

%)

Bongaarts AIDS 1989

Possible circumcision protective mechanisms

Circumcision

Anatomic effect by removal of foreskin

Reduced GUD, reduced cofactoreffects

Reduced Target cells for HIV

Impact of MC on HIV : Evidence from observational studies and RCTs

85 80 70 60 .50 1

Reduction of risk

(95% CI)

South Africa (RCT) 60 ( 76, 33)

Kenya (RCT) 59 ( 76, 30)

Uganda (RCT) 51 ( 82, 14)

Overall 58 ( 66, 48)15

17

1

1

Reduction of risk (0%)

Bailey et al. Lancet 2007; 369: 643–56

Weiss et al. AIDS 2000, 14:2361-70

Auvert et al. PLoS Med 2005(11): e298.2006

Gray et al. Lancet, 2007, 657–66

Modeling the Impact of Circumcision on HIV Prevalence/Incidence

• In SSA, 100% uptake of MC could avert 2 million new infections and 300,000 deaths over ten years

• In Soweto, 50% uptake of MC could avert 32,000 – 53,000 new infections over 20 years

• Prevalence would decline from 23% to 14%

…BUT, Can we really CIRCUMCIZE our way out of the HIV pandemic???

Sources: Williams et al., 2006; Mesesan et al., 2006

Antiretroviral Therapy

Effect on HIV Transmission

?

Topical Microbicides –Current Products

BufferGelSAVVY

Pro2000Cellulose Sulfate

PMPA/Tenofovir

ART to Prevent Transmission of HIVCohen et al. Annals Int Med, 2007

• Post-exposure prophylaxis (nPEP)

USPH Guidelines 2005

• Pre-Exposure Prophylaxis (PrEP)

• Treatment of the infected person

nPEP US Guidelines• A clinical trial to PROVE that nPEP works cannot

be developed (and it sometimes fails!!)

• CDC Guidelines generated based on consensus, lessons from macaques

MMWR Jan 21, 2005 Vol 54: 1-20 “Antiretroviral Postexposure Prophylaxis After

Sexual, Injection-Drug Use, or Other Nonoccupational Exposure to HIV in the United States”

US ALGORITHM FOR nPEP USAGEMMWR Jan 21, 2005 Vol 54: 1-20

Significant exposure risk Negligible exposure risk

<72 hours >72 hours since exposure

Source patientKnown to be HIV+

Source patient of unknown HIV status

nPEP recommended

Case-by-casedetermination

nPEPNot recommended

NVP (80%)

APV (50%)

ABC (40%)

ABC (150%)

Female Genital Tract Exposure(% blood plasma)

Dumond et al. AIDS 2007

ZDV (200%)

IDV (200%)

0 200% 400% 600%

TDF (400%)

3TC (400%)

NNRTIPINRTI

LPV (30%)

ATV (30%)

RTV (20%)

DLV (20%)

FTC (600%)ddI (100%)

SQV(ND)

EFV (0.6%)

d4T (4%)

0 2 4 6 8 10 12 140

25

50

75

100

Number of rectal exposures

% U

nin

fect

ed a

nim

als

Controls (n = 18)

Injectable FTC (n = 6)

Injectable Truvada (n = 6)

Oral Truvada (n = 6)

Oral TDF (n = 4)

PrEP in Macaques

Garcia-Lerma et al PLoS Medicine in pressGarcia-Lerma et al PLoS Medicine in press

Cohen and Kashuba PLoS Medicine inn press (editorial) Cohen and Kashuba PLoS Medicine inn press (editorial)

HIV PrEP Safety Trial CompletedPeterson et al PLoS Clin Trials 2007

• Limited toxicity, good reported adherence

• 8 on-product seroconversions observed:

2 TDF/6 placebo (p = 0.24)

• A blood specimen obtained from one of the two participants on TDF showed no evidence of resistance

Oral PrEP-Ongoing Trials

Sponsor Product/Population NSites

(Expected Results)

CDC TenofovirMale & Female IDUs

2000 Thailand (2008)

CDC TenofovirMSM

400 USA (2009)

CDC TruvadaHeterosexual men & women

1200 Botswana (2010)

NIH TruvadaMSM

3000 S.America, US, South Africa, Thailand(2011)

Oral PrEP – Planned Trials

Sponsor Product/Population N Sites

Gates Tenofovir/TruvadaDiscordant couples

2000 men,2000 women

Eastern Africa

NIH/

MTN

Tenofovir/TruvadaWomen

2400 Southern/Eastern Africa

USAID TruvadaHigh-risk women

3900 Southern/Eastern Africa

ART PrEP Human trials with TDF focused on “very high risk”

subjects hindered or stopped because of….

i) “Ethical” Considerations (Cambodia, Cameroon) Grant et. al. Science, September 30, 2005 Page-Shafer et. al. Lancet, September 2005

ii) Resistance (Malawi) Tenofovir (k65r) resistance with monotherapy

iii) Public health relevance? J. Cohen, New York Times Sunday Magazine, Jan. 2006

ART to Prevent Sexual Transmission of HIV:COUPLES REALLY MATTER!!!!!

1. Biological plausibility

-HIV SUPPRESSION in the blood and the genital tract are readily achieved

2. Expectations from “the literature”

3. HPTN052: A Clinical Trial

HIV-RNAHIV-RNA HIV-DNAHIV-DNA

00

2020

4040

6060

8080

100100

Pa

tient

s (%

) w

ithP

atie

nts

(%)

with

det

ect

ab

le H

IV in

se

me

nd

ete

cta

ble

HIV

in s

em

en

n=55n=55

n=114n=114

Controls (drug naive) Controls (drug naive)

Potent ARTPotent ART

p<0.0001p<0.0001

p=0.025p=0.025

Semen HIV in patients with suppressed Semen HIV in patients with suppressed viral loadviral load

Vernazza, Cohen Vernazza, Cohen et al.,et al., AIDS, 2000 AIDS, 2000

March 2007, Slide 62

ART Prevents HIV Transmission? Retrospective Analysis

Musicco et al. Archives Int Med 154: 1971; 1994 Castilla et al. JAIDS 40, 96, 2005

Observational Studies Kayitenkore et al. IAS, 2006 Bunnell et a. AIDS 20: 85-92, 2006

Ecological Analysis Katz et al. Am J. Public Health 92: 388, 2002 (-) Porco et al. AIDS 18:81, 2004 (+) Fang et al. JID, September 2004 (++ Montaner et al. Lancet, August 2006 (??)

March 2007, Slide 63

Bunnell et a. AIDS 20: 85-92, 2006ART offered May, 2004 in Uganda454 subjects and co-habiting partners

available for 24 month follow-upBaseline viral load (122,500 copies)

“suppressed” Increased sex, but reduced risky behaviorHIV Seroconversions reduced from

45.7/1000 py to 1/1000 pyOnly one seroconversion in 2 years

March 2007, Slide 64

HPTN 052/CHAVI007/ACTG5245HIV-infected subjects with CD4 350 to 550cells/HIV-infected subjects with CD4 350 to 550cells/µLµL

Immediate ARTImmediate ART350-550cells/uL350-550cells/uL

Deferred ART Deferred ART CD4 <250>200CD4 <250>200AZT+3TC+EFVAZT+3TC+EFV

Endpoints: i) Transmission Events Endpoints: i) Transmission Events ii) Death, TB, WHO Stage Eventsii) Death, TB, WHO Stage Events iii) ART Toxicityiii) ART Toxicity

Randomization

Timing of Trial Results

2006 2008 2009

Female Barrier- Diaphragm

Male Circumcision - Susceptibility

20102007

Microbicides – CS-1CS-2

Carraguard

Male Circumcision - Infectiousness

Microbicides• BG/Pro2000

•Pro2000• TDF

Oral PrEP - IDU

HSV-2 Treatment - Infectiousness

HSV-2 Treatment –

Susceptibility

Oral PrEP• MSM

• Heterosexual

2012

IndexPartner

Treatment

Vaccines -Adenovirus-5Vaccines -

Prime/Boost

Community VCT and HIV

Support

Oral PrEP -West Africa

Prevention of HIV

1. STD control, behavior change, condoms2. Treatment of genital herpes (Trials onging)3. Topical microbicides (Trials ongoing)4. The diaphragm (Trial completed)5. Male circumcision (Trials completed)6. Antiviral therapy (trials ongoing)7. Societal (Structural) Change: Incentives for

safer sex?

Ode to a Condom

by Myron S. Cohen

Ode to a Condom

by Myron S. Cohen

O translucent, latex sheath

You snugly guard the sword beneath

To hear your name can cause a smirk

The question is, how well you work?

But for what purpose one must ask

For you can accomplish many tasks

To prevent conception has been your goal

But to prevent infection is your truer role.

For birth control you are not great

Pregnancy can occur at a 10% rate

But for STDs let's take a look

At news not found in a medical book.

There are some differences depending on the bug

In risks for men and women after "the hug"

For gonorrhea, chlamydia, and bacterial things

The risk goes down for a man's fling

For women, alas, the news is less good

Even in the face of your mighty latex hood.

Why is this so? It is a serious plight --

Men must be taught condom wrong from condom right!

Condoms can’t work,

If they’re not put on.

Insertion sans condom,

Has no pro, only con.

TABLE 1. Problems Experienced by 47 Men During 270 Cumulative Episodes of Condom Use in the Last Month, Stratified by Risk of Transmission for STDs, HIV Infection, and Pregnancy

No. of No. of Men Events Occurrence 95% Experiencing

Problem (n=270) (%) Cl (n=47)

No direct penile-vaginal contactPut on inside-out, then flipped over and used 35 13.0 5.2-20.7 15 (31.0%)Lost erection before or after condom was put on 33 12.2 3.2-21.1 11 23.4%)Experienced allergic reaction or irritation from condom 6 2.2 0.0-5.3 3 (6.4%)Completely unrolled condom before putting on 2 0.7 0.0-2.2 1 (2.1%)Removed defective condom from package 0 -- -- 0 (0%)Tore condom with finger, jewelry or ring 0 -- -- 0 (0%)

Direct penile-vaginal contactStarted intercourse without a condom, then stopped to put on 21 7.8 2.7-12.8 8 (17.0%)Broke condom during intercourse or withdrawal 11 4.1 0.8-7.3 6 (12.8%)Started intercourse with a condom, then removed it and 7 2.6 0.2-5.0 4 (8.5%) continued intercourseCondom fell off during intercourse or withdrawal 4 1.5 0.0-3.2 3 (6.4%)

STDs = Sexually transmitted diseases; HIV = human immunodeficiency virus, CI = confidence interval

Warner L, Clay-Warner J, Boles J, Williamson J. Assessing condom use practices. Sex Transm Dis 1998; 25(6):273-277.

Look at your package, look at your date;

If you are damaged one tempts the fates

Roll you on smoothly, expunge air at your tip,

Take you off if there is the smallest rip (drip).

And latex is tricky;

It’s destructible stuff.

So don’t lubricate with oil;

Water is enough.

And after the "love", while you are still in place,

You must be removed at a rapid pace

Gently unrolled and safely tied

Access for the milky elixir completely denied.

AND WHAT ABOUT AIDS, THE ULTIMATE FOE

Can you help? Is it so?

The answer is clear,

And should bring great cheer.

The spread of the virus has been carefully reviewed

In couples who used you and those who eschew you

When you are used transmission nears zero

Your rubbery face has the smile of a hero

0.10.1 11 1010

Fischl 1987Fischl 1987

Ngugi 1988Ngugi 1988

Nzila 1989Nzila 1989

Allen 1992Allen 1992

Laurian 1989Laurian 1989

deVincenzi 1994deVincenzi 1994

Saracco 1993Saracco 1993

Plummer 1991Plummer 1991

Deschamps 1996Deschamps 1996

Feldblum 1994Feldblum 1994

Relative risk (Log10) of HIV infection among heterosexual couples using condoms

From W. Cates in Holmes, K.K. From W. Cates in Holmes, K.K. et alet al., (eds) Sexually Transmitted Diseases, 3., (eds) Sexually Transmitted Diseases, 3 rdrd ed. New York, McGraw-Hill, 1998. ed. New York, McGraw-Hill, 1998.

Monogamy is good, abstinence is best

You can't catch disease, if you give sex a rest.

But if "love" is your destiny, and you are fated to “dance”

Take heed because condoms are better than chance.

A. Fauci, 2006