# Presentation: 175692

## Amplified Transmission of HIV:  Missing Link in the Pandemic?

- Myron S. Cohen, MD
- J. Herbert Bate Professor
- Medicine, Microbiology and Immunology and Epidemiology
- Director, UNC Infectious Diseases
- The University of North Carolina at Chapel Hill

## 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 HIV:Biological Requirements

- Infectious				Susceptibility
***Inoculum (concentration)******	******Hereditary resistance***
***Phenotypic factors******	******	******Innate resistance***
***	******	******	******	******	******	******Acquired (immune)***
***	******	******	******	******	******	******	******resistance***
- ...*from Cohen and Galvin*
*Nature Microbiology Reviews 2:33-42, 2004*

## semen

- lamina propria
- dendritic cell
- CD4+
- CCR5+
- DC-SIGN+

- exposure
- at mucosal
- epithelium

- T cell

- CD4

- CCR5

- DC-SIGN

- migration
- to lymphoid organs

- “Hand-Off” of HIV-1 from
- dc to T cells via DC-SIGN
- Activation State of T cells?

## Estimated HIV transmission probability

- Chakraborty *et al*., AIDS 2001

- 0.004

- 0.008

- 0.012

- 0.016

- 3

- 3.5

- 4

- 4.5

- 5

- 5.5

-  Log10 Seminal HIV RNA in one ejaculate

- Probability of transmission

- 25%

- 50%

- 75%

- Cervical
- CCR5
- Receptor
- Density

**Notes:**
Here,
 X axis is ....
Y axis is ......
explain three lines ......

Explain the slope change after 4.5 log1- value of RNA values. 

## Routes of Exposure and H.I.V. 

**INFECTION ROUTE****	****	****RISK OF INFECTION**
**Sexual Transmission**
- a.  	Female-to-male transmission............1 in 700 to 1 in 3,000
- b.  	Male-to-female transmission..............1 in 200 to 1 in 2,000
- Male-to-male transmission................1 in 10 to 1 in 1,600
- Fellatio??................................... .0 (CDC) or 6% (SF)
**Parenteral transmission**
- Transfusion of infected blood.............95 in 100
- Needle sharing...............................1 in 150
- c.	Needle stick...................................1 in 200
- d.	Needle stick /AZT PEP.....................1 in 10,000
**Transmission from mother to infant**
- a.  	Without AZT treatment...................1 in 4
- b.  	With AZT treatment......................Less than 1 in 10
*Royce, Sena, Cates and Cohen, NEJM 336:1072-1078, 1997*

## HIV Prevalence by Age and Gender among South African youth age 15-24 years

**2.6%**

**9.4%**

**2.0%**

**6.0%**

**2.1%**

**4.0%**

**3.6%**

**4.1%**

**2.3%**

**11.0%**

**12.2%**

**7.9%**

**5.8%**

**13.8%**

**4.1%**

**14.4%**

**31.2%**

**25.0%**

**28.9%**

**26.3%**

**0%**

**5%**

**10%**

**15%**

**20%**

**25%**

**30%**

**35%**

**40%**

**45%**

**50%**

**55%**

**Age 15**

**Males**

**Females**

**95% Confidence Interval**

**Age 16**

**Age 17**

**Age 18**

**Age 19**

**Age 20**

**Age 21**

**Age 22**

**Age 23**

**Age 24**

- Pettifor A, et al. AIDS 2005, 19: 1525-1534.

## Coital Frequency per Month by 

- 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

**Coital frequency per Month**

## Hypothesis

-  1) Estimated transmission rates from earlier studies are too low to explain the epidemic
- 2) HIV transmission is intermittently
-    AMPLIFIED by increased genital tract shedding
-  3) AMPLIFIED transmission is critical to the spread of HIV

## Factors that AmplifyTransmission of HIV 

*Infectiousness*
- Stage of Disease ... ACUTE INFECTION?
- Other Co-infections
- 	-Malaria?
- 	-Helminthic infections?
- 	-Tuberculosis?
-      -STDs
-  Genetic factors
*Susceptibility*
- STDs
- Bacterial vaginosis
- Inate immunity
- Genetic factors
**    **
** **

## Sexual Transmission of HIV (Cohen and Pilcher, JID May 2005)

- (Log10 copies/ml)

- 1/1000 -
- 1/10,000

- 1/500 -
- 1/2000

- 1/100-
- 1/1000

- Risk of Transmission
- Reflects **Genital **Viral Burden

- 1/30-
- 1/200

- Sexual Transmission of HIV (*Cohen and Pilcher, JID May 2005)*

## Wawer, JID 2005

**Wawer, JID 2005**

## Diagnosing Acute HIV Infection:An Alternative Approach  

## The acute retroviral syndrome

- 49-89% of patients “symptomatic” within 3 mos.
- 			     _*Schacker*_*	**     *_*Kinloch-de Loes*_
- Fever		93%		87%
- Fatigue		93		26
- Pharyngitis	70		48
- Weight loss	70		13
- Myalgias		60		42
- Headache	            55		39
- ....BUT LESS THAN 1,000 subjects with acute/early HIV have been reported out of 60,000,000 infected!!

## HIV viremia during early infection

**HIV RNA (plasma)**

**HIV Antibody**

**11**

**HIV p24 Ag**

**16**

**22**

*Ramp-up viremia*
*DT = 21.5 hrs*

-  *1**st** gen*

*2**nd** gen*

*3**rd** gen*

*p24 Ag EIA* -

*HIV MP-NAT* -

*HIV ID-NAT* -

*Peak viremia: 10**6**-10**8** gEq/mL*

- “blip” viremia

*Viral set-point: 10**2 -**10**5** gEq/mL*

## Pooling Serum Specimensto Detect HIV RNA(Pilcher et al JAMA 288:216-221, 2002)

-    A

- Individual testing on 10 specimens

- 10 pools of 10 screened

- 20 Screening Pools Tested
- N=2000

- Pooling Serum Specimensto Detect HIV RNA(*Pilcher et al JAMA* *288:216-221, 2002)*

## NC Population Testing Program 2003n=109,250 at risk clients (9 months)Pilcher et al. NEJM 352:1873, 2005

**NAAT**

**+**

**-**

**F/U Testing**
**(Ab+NAAT)    **

**-**

**+**

***Acute HIV***

***HIV Negative***

**-**

**EIA/WB    **

**+**

** ****LS-EIA**
** ****at UNC**

***Likely recent***

**+**

***Unknown ***
***duration***

**-**

***Long Term HIV Positive ***

- NC Population Testing Program 2003*n=109,250 at risk clients (9 months)**Pilcher et al. NEJM 352:1873, 2005*

**106**

**477**

**23**

**25**

## Viral Loads at Initial Detection

- 0

- 1

- 2

- 3

- 4

- 5

- 6

- 7

- 8

- 9

- 10

- Established HIV+           (n=66)

- Acutely HIV +              (n=21)

**Log HIV RNA cp/ml**

-  median      209,183

- 29,347

**Notes:**
As would be expected, the average viral loads for patients with acute HIV were higher than for a comparison group of newly diagnosed HIV infections identified by having a positive HIV Antibody test

## Slide 19

## AHI: Recruitment of Sexual Partners

-    Three named partners successfully contacted per acute patient (2.5 HIV-, 0.5  HIV+):
-     Established HIV, AHI, HIV-, Recently Exposed?

- HIV Positive Partners

- HIV Negative Partners

## Infection by testing site: NC(Pilcher et al. NEJM in press)

- Infection by testing site: NC*(Pilcher et al. NEJM in press)*

- 0

- 50

- 100

- 150

- 200

- 250

- STD

- HIV
- Testing

- “Other”

- Prison,
- Jail

*N= 44656       11688           7575        3053*

- Not shown:  Prenatal/OB FP Drug Treatment General Medical TB Field visits

- Acute
- Recent
- Unknown Duration

- 16/23 Acute Infections from STD Clinics

## Do STDs Play a Major Role?Incident Transmission of HSV-2   Incident Transmission of Syphilis ...ARE VERY STRONGLY ASSOCIATED WITH ACQUISITION OF HIV-1

## 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

**Notes:**
Small landlocked country in Southern Africa bordered by Tanzania, mozambique, and Zambia. IT has a population of about 10 million of which 90% lives in rural area.  It is among the poorest countries in the world with a GNP of about $200.  Like other countries in  sub saharan africa, it has been devastated by the AIDS epidemic with nearly 1 million people infected with HIV with an adult prevalence rate of 15%.

## Tidziwe Center 

**Tidziwe Center **
**Lilongwe Central Hospital**
**Lilongwe, Malawi**

## Acute HIV Infection and STDsPilcher et al. AIDS 18:1-8, 2004

- 1,361 men screened in STD and Dermatology Clinics in Lilongwe Malawi
- 47% antibody + (chronic HIV Infection)
- 2.1% (28) with acute HIV (antibody -, RNA +)
-          Inguinal nodes: 11.4% acute HIV
-          Genital ulcer (HSV):  7.8% acute HIV
-          CSW exposure: 9.1% acute HIV
**   ****Acute HIV was detected ONLY in symptomatic STD patients (!!) implying co-transmission or “staged” transmission of an STI followed by HIV,  or vice-versa. **** **

## Viral Loads in Malawi: Chronic and Acute HIV Infection

**0**

**2**

**4**

**6**

**8**

**10**

**Log HIV RNA cp/ml**

**HIV Ab+**

**HIV Ab- (acute)**

- Viral Loads in Malawi: Chronic and Acute HIV Infection

## Acute HIV Detection (Malawi)

- All attendees to
- STD clinic

- Refusals
- <18 years old
- Admitted (too ill)
- Persistent (non-incident) STD

- 345 rapid test
- Positive (41%)

- 476 rapid test
- Negative (57%)

- 15 rapid test
- Discordant (2%)

- 8 RNA
- positive

- 5 RNA
- positive

- 836 men and
- women HIV tested

## STD Syndromes in AHI 2005 (21/1,441)

| STI Syndrome | OR | 95% CI | P-value |
| --- | --- | --- | --- |
| Both sexes  |  |  |  |
|     Genital ulcer disease | 6.69 | (2.54, 17.63) | <0.0001 |
|              GUD with adenopathy  | 11.96 | (3.29, 43.42) | <0.0001 |
|              GUD without adenopathy  | 7.33 | (2.18, 24.68) | 0.0002 |
|     Bubo | 1.81 | (0.41, 8.02) | 0.43 |
|     Warts | 1.30 | (0.17, 10.00) | 0.8 |
|  |  |  |  |
| Males Only |  |  |  |
|     Urethral Discharge | 0.96 | (0.35, 2.62) | 0.94 |
|     Balanitis | 0.91 | (0.20, 4.06) | 0.90 |
|  |  |  |  |
| Females Only |  |  |  |
|     PID | 3.91 | (0.40, 38.11) | 0.21 |
|     GUS – High Risk | 1.55 | (0.16, 15.19) | 0.70 |
|  |  |  |  |

## Predicting Acute HIV Infection

- Area under ROC curve = 0.895

**Notes:**
The variables surviving the final round of elimination are shown here, with their adjusted PORs in the final, combined model, as well as the associated risk scores. 

A score of 1 corresponded to >1 sex partner in the previous 2 months, fever in the past month, and body ache in the past month

A score of 2 corresponded to diarrhea in the past month and clinical presentation of GUD  

A score of 4 corresponded to discordant rapid test results.  

The area under the ROC curve for this model was 0.895, indicating almost 90% accuracy in predicting AHI and HIV-negative status.

## Viral Loads in Blood and Semen        During Acute HIV Infection

- 2

- 3

- 4

- 5

- 6

- 0

- 1

- 2

- 4

- 8

- 12

- 16

**STUDY WEEK**

- BLOOD

- SEMEN

**MEAN log10 HIV-1 RNA cp/ml**

## HIV transmission prob. per male-female act: fold-change relative to wk 16 (calculated after Chakraborty H, et al AIDS 2003)

**Weeks from Testing Positive for AHI**

**Fold-change vs. wk 16**

- 0

- 2

- 4

- 6

- 8

- 10

- 12

- 14

- 16

- 1

- 2

- 4

- 8

- 12

- 16

**Notes:**
Based on our 

## Sexual Transmission of HIV (Cohen and Pilcher, JID May 2005)

- (Log10 copies/ml)

- 1/1000 -
- 1/10,000

- 1/500 -
- 1/2000

- 1/100-
- 1/1000

- Risk of Transmission
- Reflects **Genital **Viral Burden

- 1/30-
- 1/200

- Sexual Transmission of HIV (*Cohen and Pilcher, JID May 2005)*

## Slide 33

## HPTN 052 Baseline HIV RNA

| 
Site | HIV RNA at Enrollment (log 10 scale) |  |
| --- | --- | --- |
|  | Mean | SD |
| Porto Alegre, Brazil | - | - |
| Rio de Janeiro, Brazil | 4.4 | 0.5 |
| Chennai, India | 4.8 | 0.5 |
| Pune, India | 4.3 | 0.6 |
| Blantyre, Malawi | 5.3 | 0.3 |
| Lilongwe, Malawi | 4.6 | 0.7 |
| Chiang Mai, Thailand | 4.5 | 0.6 |
| Boston, US | 4.5 | - |
| Harare, Zimbabwe | 4.7 | 0.0 |
| Total | 4.6 | 0.6 |

## Sexual Transmission of HIV

- (Log10 copies/ml)

- 2

- 3

- 4

- 5

**Risk of Transmission**
**Reflects *****Genital***** Viral Burden**** **

**1/30-**
**1/200**

**1/1000 - **
**1/10,000**

**1/500 - **
**1/2000**

**1/100-**
**1/1000**

## Effect of STD Treatment on HIV-1 RNA in 

**Effect of STD Treatment on HIV-1 RNA in **
**Semen of Urethritis Patients**
***Cohen et al. Lancet 349: 1868, 1997***

- Wk1

- Wk2

- Wk3

- Wk1

- Wk2

- Wk3

- 20

- RNA copies / ml (in thousands)

## Acute HIV and STD episodes(Cohen and Pilcher, JID, 2005

- (Log10 copies/ml)

- Acute HIV and STD episodes*(Cohen and Pilcher, JID, 2005*

## Prevention of HIV

- 1. STD control, behavior change, condoms
- 2. STD interventions (trials ongoing)
- 3. Vaccines (trials ongoing)
- 4. Treatment of Bacterial Vaginosis (??)
- 5. Topical microbicides (trials ongoing)
- 6. The diaphragm (trials ongoing)
- 7.  Male circumcision (trials ongoing)
- 8.  Antiviral therapy (trials ongoing)
- 9.  Societal (Structural): “Incentives” for safer sex?

## Vaccines for Prevention of HIV Infection

**Good News:**
- 	HIV proteins are immunogenic
- 	Animal success stories and clues to immunity
**Bad News:**
- 	No reliable surrogates of immunity
-    Short lived immunity
-    VAXGEN Failure
- 	The Cost : Benefit ratio

## Potential end-points of HIV-vaccine efficacy trials

*UNAIDS–97100   1 August 1998*

- “normal” infection
- with variable levels
- of viral load

- no protection

- no infection

- protection against HIV
- sterilizing 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

## Volunteers Needed

- for an HIV Research Study

- Announcing an Exciting New Vaccine Development Study for
- HIV **Positive** or HIV **Negative** Person

- This is a two year study designed to look at
- the immune system to determine factors
- that lead to HIV transmission.

- HIV Research Volunteers
-     Make a Difference.

- For more information, contact:
- CHAVI@med.unc.edu
- or 919-966-8533

- Help Us Learn More.  HIV Research is Ongoing
- For more information on this and other studies, go to: WWW.ID.UNC.EDU/ACTU

## The Center for HIV Vaccine Immunology (CHAVI)

**Progress in HIV Vaccine research requires: **
**  **
- Subjects with acute HIV infection for longitudinal studies
- Large numbers of HIV “transmission pairs”
- HIV exposed, uninfected subjects...defined as???
- Subjects to study the genetic components of  HIV transmission and resistance
- Genital tract (mucosal) samples, understanding

## ART to Prevent Sexual Transmission of HIV

- Post-exposure prophylaxis (nPEP)
-    *USPH Guidelines 2003*
- Pre-exposure Prophylaxis (PREP)
-    *RCTs with tenofovir planned*
- Treatment of the infected person
-     *HPTN052: A study of  1750 discordant couples with early vs. delayed ART *

## Male Genital Tract Exposure percent of blood plasmaKashuba et al. and  CROI 13 Abstract 569 (Vourvahis), 13th CROIAbstracts 396 (Stekler), Abstract 618 (Katzenstein)  

**Male Genital Tract Exposure*** ****percent of blood plasma******Kashuba et al. and  CROI 13 Abstract 569 (Vourvahis), 13******th****** CROI******Abstracts 396 (Stekler), Abstract 618 (Katzenstein)  ***

**NNRTI**

**PI**

**FI**

**NRTI**

## Semen HIV in patients with suppressed 

**n=55**

**n=114**

**Controls (drug naive) **

**Potent ART**

**p<0.0001**

**p=0.025**

- Semen HIV in patients with suppressed
- viral load

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

## Slide 46

## Conclusions

- Genital tract viral burden determines HIV transmission
- STDs and HIV and are likely sequentially transmitted and large numbers of subjects with acute HIV infection will present with STDs, especially GUD
- Recurrent risk behavior(s) allow subjects with established HIV infection to be detected in STD treatment settings
- HIV transmission is amplified early and late in HIV infection, and these subjects help to fuel the epidemic
- HIV prevention WILL increasingly focus on the most contagious subjects, and biological and behavioral interventions WILL be developed to reduce HIV  transmission probability