the body pro the hiv resource for health professionals faculty: anita radix, m.d., m.p.h. associate...

THE BODY PROThe HIV Resource for Health Professionals

Faculty: Anita Radix, M.D., M.P.H. Associate Clinical Professor at theUniversity of Connecticut Health Center

The Body PRO Covers the XVII InternationalAIDS Conference (AIDS 2008)Mexico City; August 3-8, 2008

Copyright © 2008 Body Health Resources Corporation. All rights reserved.

This activity is jointly sponsored by Postgraduate Institute for Medicine and The Body PRO.

Anita Radix, M.D., M.P.H.

Recent Developments inHIV Prevention

The Body PRO

Recent Developments in HIV Prevention: Highlights From AIDS 2008

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Faculty for This ActivityFaculty for This Activity

Anita Radix, M.D., M.P.H.

Anita Radix, M.D., M.P.H., is an HIV clinician at Callen Lorde Community Health Center in New York and an associate clinical professor at the University of Connecticut Health Center.

Dr. Radix trained in internal medicine, infectious diseases and public health at the University of Connecticut Health Center. While living in the Caribbean in the 1990s, she directed a health department in the Netherlands Antilles and implemented preventive and research programs pertaining to HIV.

Dr. Radix is an advisory member of the Caribbean Vulnerable Communities, a coalition of organizations and individuals working in rights-based HIV prevention, care, treatment and support in the Caribbean.

DisclosuresDr. Radix serves on speakers bureaus for GlaxoSmithKline.

This activity is supported by educational grants from

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AgendaAgenda

• HIV epidemic in the United States

• Prevention strategies

– Herpes simplex virus (HSV) suppression to reduce HIV

incidence

– Status of pre-exposure prophylaxis (PrEP) studies

– Antiretroviral therapy (ART) as secondary prevention

– HIV superinfection in seroconcordant couples

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HIV Incidence in the U.S. IsHigher Than Previously ExpectedHIV Incidence in the U.S. IsHigher Than Previously Expected

• HIV incidence in the U.S. previously was measured via an indirect method.

• The BED HIV-1 capture enzyme immunoassay classifies infections as recent or long-standing.

• In 2006, an estimated 56,300 (95% confidence interval [CI], 48,200 - 64,500) new infections occurred.

• The estimated incidence rate was 22.8 per 100,000 persons (95% CI, 19.5 - 26.1).

• Forty-five percent of new infections were among black individuals and 53% among men who have sex with men.

Adapted from H. Irene Hall et al. JAMA. 2008;300:520-529.

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Estimated Percentage of NewHIV Infections, by Sex, 2006*Estimated Percentage of NewHIV Infections, by Sex, 2006*

Men

73%

Women

27%

N = 56,300

*50 States and District of Columbia

Kevin Fenton. AIDS 2008; abstract WEAC0302. Reprinted with permission.

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Estimated Number of New HIV Infections, by Sex, 1977-2006*Estimated Number of New HIV Infections, by Sex, 1977-2006*

Total

Males

Females



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7Estimated Percentage of New HIV

Infections, by Transmission Category, 2006*

Estimated Percentage of New HIV

Infections, by Transmission Category, 2006*

Men who have sex with men

53%Men who have sex with men

and inject drugs 4%

Injection drug users 12%

Heterosexual contact

31%

N = 56,300



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8Estimated Number of New HIV Infections, by Transmission Category, 1977-2006*

Estimated Number of New HIV Infections, by Transmission Category, 1977-2006*

MSM

IDU

HET



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9Estimated Percentage of New HIV Infections, by Race/Ethnicity, 2006*

Estimated Percentage of New HIV Infections, by Race/Ethnicity, 2006*

White35%

Black45%

Hispanic 17%

American Indian/Alaska Native 1%

Asian/Pacific Islander2%

N = 56,300

*50 States and District of ColumbiaKevin Fenton. AIDS 2008; abstract WEAC0302. Reprinted with permission.

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Estimated Rates of NewHIV Infections, 2006*Estimated Rates of NewHIV Infections, 2006*

22.8

11.5 10.314.6

29.3

83.7

0

10

20

30

40

50

60

70

80

90

Total White Black Hispanic A/ PI AI/ AN

Race/ ethnicity

Rate

per

100,0

00

Total male: 34.3 per 100,000

Total female: 11.9 per 100,000*50 States and District of Columbia


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Estimated Percentage of NewHIV Infections, by Age, 2006*Estimated Percentage of NewHIV Infections, by Age, 2006*

13-29 34%

30-39 31%

40-49 25%

50-99 10%


N = 56,300


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HIV in the U.S.: SummaryHIV in the U.S.: Summary

• HIV/AIDS incidence is increasing.

• The highest HIV rates are among men who have sex with men (MSM), African Americans and Hispanics.

• One quarter of those with HIV infection remain undiagnosed.

• Prevention is key, but more effective prevention interventions need to be developed.

• HIV testing needs to be fully routinized.

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Four Prevention OpportunitiesFour Prevention Opportunities

YEARS

Treatment of HIVReduced Infectivity

INFECTED

YEARS

UNEXPOSED

Behavioral,Structural

Circumcision

Condoms

HOURS

VaccinesART PrEP

Microbicides

EXPOSED (precoital/coital)

72h

VaccinesART PEP

EXPOSED (postcoital)

Myron Cohen. AIDS 2008; abstract TUPL0102. Reprinted with permission.

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0.004

0.008

0.012

0.016

3 3.5 4 4.5 5 5.5 Log10 Seminal HIV RNA in One Ejaculate

Pro

babi

lity

of T

rans

mis

sion

Chakraborty et al. AIDS 2001

Viral Concentration Really MattersViral Concentration Really Matters


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Powers et al. Lancet ID, 2008

HIV TransmissionEfficiency by CofactorHIV TransmissionEfficiency by Cofactor


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Acute HIV Infection

Acute HIV Infection

& STD Co-infection

& STD Co-infection

STD Episode

STD Episode

STD Episode

STD EpisodeAIDSAIDS

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

10

8

6

4

2

0

HIV

RN

A i

n S

emen

(Lo

g10

Co

pie

s/m

L)

Amplified Transmission of HIVAmplified Transmission of HIV


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Does Suppression of HSV-2 Prevent HIV Acquisition?Does Suppression of HSV-2 Prevent HIV Acquisition?

• Meta-analysis of 19 longitudinal studies suggests that HSV-2

increases HIV acquisition in men and women1

• Prevalent HSV-2 infection and HIV acquisition:

• Men Relative Risk (RR) 2.7 (95% CI, 1.9 - 3.9)

• Women RR 3.1 (95% CI, 1.7 - 5.6)

• MSM RR 1.7 (95% CI, 1.2 - 2.4)

1. Esther E. Freeman et al. AIDS. 2006;20:73-83.

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Effect of HIV on HSV-2

• Alters clinical presentation & frequency of HSV-2 shedding

• Longer duration of lesions (CD4 < 200)

HSV-2 acquisition & transmission

Effect of HSV-2 on HIV

HIV acquisition

HIV levels in plasma & genital tract

HIV transmission

HSV-2HIV

Interactions: HSV-2 and HIVInteractions: HSV-2 and HIV

Connie Celum et al. AIDS 2008; abstract THAC0302. Reprinted with permission.

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HSV Suppressive TrialsHSV Suppressive Trials

Location Tanzania Southern Africa, U.S. and Peru

Trial

Randomized, double-blind,placebo-controlled trial of HSV-2

suppressive therapy with acyclovir400 mg vs. placebo

HPTN 039: randomized, double-blind, placebo-controlled trial of HSV-2 suppressive therapy with

acyclovir 400 mg vs. placebo

Participants High-risk womenWomen in Southern Africa

MSM in U.S. and Peru

Adapted from Deborah Watson-Jones et al. AIDS 2008; abstract THAC0304.

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Followed to 12-30 Months Interview, Tablets, Bloodand STI SamplesEvery Six Months

Tablets, Interview andBlood Sample EveryThree Months

Study Design(Tanzanian Acyclovir Study)Study Design(Tanzanian Acyclovir Study)

Randomized toScreening Round forHSV-2 and HIV AB

Mapping of Sites Mobilization

• Acyclovir 400 mg BID• Syndromic Sexually Transmitted Infection (STI) Prescription (Rx)• Condoms, Family Planning (FP) and Voluntary Counselling and Testing (VCT)

• Placebo BID• Syndromic STI Rx• Condoms, FP & VCT

BothRandomizedGroups


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Follow-Up and HIV IncidenceFollow-Up and HIV Incidence

Acyclovir Placebo Total

Number Enrolled (%) 400 421 821

Follow-Up Status 776

Median Follow-Up 2.54 years (0.1-2.78)

HIV Seroconverted 30 (8%) 33 (8%) 63 (8%)

HIV Incidence Rate/100 Person-Years

4.29 (3.00-6.13) 4.24 (3.01-5.97) 4.27 (3.33–5.46)

Person-Years of Follow-Up 699 778 1,477

Rate Ratio 1.01 (0.62-1.66) -

* Non-attenders (includes women who did not extend and lost to follow-up)


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HIV- HSV-2+Heterosexual Women

and

HIV- HSV-2+ MSM

Acyclovir 400 mg BID Matching Placebo BID

Randomize

Harare, ZimbabweLusaka, ZambiaJohannesburg, South Africa

Lima, Iquitos, Pucallpa: PeruSeattle, San Francisco, NYC

Primary endpoint: HIV infection

Both arms received episodic acyclovir for genital ulcer disease and risk-reduction counselling.

HPTN 039: HSV-2 Suppressive Therapy to Prevent HIV AcquisitionHPTN 039: HSV-2 Suppressive Therapy to Prevent HIV Acquisition

Jorge Sanchez et al. AIDS 2008; abstract THAC0302. Reprinted with permission.

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11,731 assessed for eligibility11,731 assessed for eligibility

3,277 randomized3,277 randomized

1,637 assigned to intervention1,637 assigned to intervention

1,640 assigned to control1,640 assigned to control

8 HIV +3 duplicate45 HSV-2 -




1,581 included in analysis1,581 included in analysis

1,591 included in analysis1,591 included in analysis

8,454 ineligible8,454 ineligible

HPTN 039: Study DesignHPTN 039: Study Design


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Overall Hazard Ratio (HR) 1.16 (95% CI, 0.83-1.62); P = .39

HPTN 039: Time to HIV byStudy ArmHPTN 039: Time to HIV byStudy Arm


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Despite evidence that HSV-2 increases HIV acquisition in

men and women, acyclovir 400 mg BID did not reduce the

risk of HIV acquisition among high-risk HSV-2 seropositive

MSM and women in these studies.

Possible issues:

• Poor adherence to regimen

• Acyclovir may not have been optimal treatment

Suppression of HSV-2 asHIV Prevention: DiscussionSuppression of HSV-2 asHIV Prevention: Discussion

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Four Prevention Opportunities: PrEPFour Prevention Opportunities: PrEP

YEARS


INFECTED

YEARS

UNEXPOSED


Circumcision

Condoms

HOURS

VaccinesART PrEPMicrobicides

EXPOSED

72h

VaccinesART PEP

EXPOSED (postcoital)(precoital/coital)


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Antiretroviral (ARV) PrEP forHIV Prevention Antiretroviral (ARV) PrEP forHIV Prevention

• Data suggesting that ARV PrEP may be effective– ARVs for PMTCT [prevention of mother-to-

child transmission of HIV]– Post-exposure prophylaxis for HIV– Monkey models for SHIV transmission

• Available ARVs appear safe

• Available ARVs can be used once daily– TDF: tenofovir disoproxil fumarate– FTC: emtricitabine– TDF/FTC

Timothy Mastro. AIDS 2008; abstract THSY0603. Reprinted with permission.

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28Data From Monkey Studies at CDC:Prevention of Rectal SHIV Transmission by Chemoprophylaxis With ARVs

Data From Monkey Studies at CDC:Prevention of Rectal SHIV Transmission by Chemoprophylaxis With ARVs

0 2 4 6 8 10 12 140

25

50

75

100

Control (n = 18)

FTC (subcut, n = 6)p = 0.021, [HR = 3.9]

FTC/Tenofovir (subcut, n = 6)

FTC/TDF (oral, n = 6)p = 0.0075, [HR = 7.8]

TDF (oral, n = 4)*p = 0.3

Number of rectal exposures

% U

nin

fec

ted

an

ima

ls


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One Completed Clinical TrialOne Completed Clinical Trial

• West Africa Phase II PrEP Trial (FHI/BMGF)

• RCT [randomized control trial]: daily TDF 300 mg and placebo

• Women (N = 936) in Ghana, Cameroon and Nigeria

• Conducted June 2004 - March 2006

• No evidence of increased clinical or laboratory adverse effects

• No evidence of risk compensation

• Inadequate power to assess efficacy– 8 HIV seroconversions: 2 TDF, 6 placebo– RR = 0.35, P = .24


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Ongoing PrEP TrialsOngoing PrEP Trials

• Tenofovir Extended Safety Study (CDC)

• Bangkok Tenofovir Study (CDC)

• Botswana TDF2 (TDF/FTC) Trial (CDC)

• iPrEX (UCSF/NIAID/BMGF)

• Partners PrEP (UW/BMGF)


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Summary of Ongoing and Planned PrEP StudiesSummary of Ongoing and Planned PrEP Studies

Sponsor/Funder

Study Product Population N SitesExpected Start/

Results

CDC TDF MSM 400 U.S. 2009

CDC BTS TDFMale and Female

Injection Drug Users

2,400 Thailand 2009?

CDC TDF-2 TDF/FTCMale and Female

Heterosexuals1,800 to

2,000Botswana 2010?

UCSF, NIH, BMGF iPREX TDF/FTC MSM 3,000Brazil, Equador,

Peru, U.S., Other2010

UW, BMGFPartners

PrEPTDF

TDF/FTC

Discordant Heterosexual

Couples3,900 Kenya, Uganda 2011

FHI, USAID/BMGF

FEM-PrEP

TDF/FTC Women 3,900Kenya, Malawi, South Africa,

Tanzania2008/2012

MTN, NIAID VOICETDF

TDF/FTCTDF Gel

Women 4,200Malawi, South Africa,

Uganda, Zambia, Zimbabwe

2009/2012

Adapted from Timothy Mastro. AIDS 2008; abstract THSY0603.

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Total Participants in the Seven PrEP TrialsTotal Participants in the Seven PrEP Trials

Total Participants in the Seven PrEP Trials

Heterosexual Women 11,050

Heterosexual Men 2,950

MSM 3,400

Injection Drug Users 2,400

TOTAL 19,800

Adapted from Timothy Mastro. AIDS 2008; abstract THSY0603.

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Four Prevention Opportunities:ART for Secondary PreventionFour Prevention Opportunities:ART for Secondary Prevention

YEARS


INFECTED

YEARS

UNEXPOSED


Circumcision

Condoms

HOURS

VaccinesART PrEPMicrobicides

EXPOSED (precoital/coital)

72h

VaccinesART PEP

EXPOSED (postcoital)


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ART for Secondary PreventionART for Secondary Prevention

• Strong biological plausibility for men and women

• Retrospective clinical studies

• Observational studies of couples

• Ecological population studies

Cohen et al. Annals Int Med 2006

Vernazza, al., AIDS, 2000Cu-Uvin et al., JAIDS, 2006

Men Women

0

20

40

60

80

100

Pat

ient

s (%

) W

ith D

etec

tabl

e H

IV in

Gen

ital S

ecre

tions

Not on ARTNot on ARTOn ARTOn ART

Larry Bragg. AIDS 2008; abstract MOPE0404. Reprinted with permission.

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Secondary Prevention:The Swiss RecommendationsSecondary Prevention:The Swiss Recommendations

“HIV-positive individuals without additional sexually transmitted diseases (STDs) and on effective antiretroviral therapy are sexually non-infectious.” —The Swiss National AIDS Commission

Pietro Vernazza et al. L Bulletin des médecins suisses. 2008;89:165-169.

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Guidelines state that the risk of HIV transmission during sex without a condom is less than 1:100,000 if the HIV-infected individual:

• Is fully compliant with the antiretroviral therapy

• Evaluated regularly by the treating physician

• Has a viral load that has been undetectable since at least six months (< 40 copies/mL)

• Has no additional sexually transmitted diseases present


Pietro Vernazza et al. L Bulletin des médecins suisses. 2008;89:165-169.

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Attia et al conducted a

meta-analysis to estimate

the risk of HIV

transmission among

serodiscordant couples.

No studies

fulfilled the

exact criteria

of the Swiss

statement.

Out of 252

published articles

and abstracts, only

14 were found to

be eligible.

Adapted from Suzanna Attia. AIDS 2008; abstract THAC0505.


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Can Unprotected Sex Be Safe?Study SummaryCan Unprotected Sex Be Safe?Study Summary

Characteristic Couples (N = 3,168) Studies ( N = 14) Transmissions (N = 307)

Region

Africa 1,822 4 237

Asia and South Asia 387 2 21

Europe 424 4 10

North America 58 2 10

South America and Caribbean 495 2 29

Population

Heterosexual 3,145 13 303

MSM 46 1 4

Data About HAART in theHIV-Infected Partner?

Pending 1,372 6 154

Yes, number on HAART 428 of 1,814 8 153

Data About STI in theHIV-Infected Partner

Pending 2,130 7 93

Yes, number on STI Pending ? of 1,056 7 214Adapted from Suzanna Attia. AIDS 2008; abstract THAC0505.

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Can Unprotected Sex Be Safe?Meta-AnalysisCan Unprotected Sex Be Safe?Meta-Analysis

No. of Studies Identified

Group Transmissions PY1 Rate/100 PY1

(95% CI)

0On HAART With Viral Load < 400 copies/mLand No Other STI

- - -

12

On HAART With Viral Load < 400 copies/mLand STI Status Unclear

0 283.2 0 (0-1.06)

13

HAART-Naive With Viral Load < 400 Copies/mL and No Other STI

0 10.3 0 (0-29.08)

44

HAART-Naive With Viral Load < 400 Copies/mL and STI Status Unclear

1 610.3 0.16 (0.02 – 1.16)

1Person-years of follow-up2Castilla J et al. JAIDS. 2005.3Ragni M et al. JAIDS & Human Retrovirol. 1998.4Quinn TC et al. NEJM. 2000; Operskalski E et al. Am J Epidemiol. 1997; Melo M et al. Sex Transm Dis. 2008 (in press); Castilla J et al. JAIDS. 2005 (1 seroconversion at index case viral load 362 copies/mL)


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Can Unprotected Sex Be Safe?DiscussionCan Unprotected Sex Be Safe?Discussion

Although no reports of HIV transmission occurred by any individual with an HIV RNA of less than 40 copies/mL

• No data exists for anal sex / MSM

• Lack of data about concurrent condom use or sexual practices

• Occasional spikes in viral load may occur in individuals adherent to ART

• People with other sexually transmitted infections, such as herpes, can be asymptomatic, yet still be capable of transmitting or contracting HIV

• Unable to accurately quantify the risk of transmission using the Swiss parameters


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Positive Partners Study:Serosorting and SuperinfectionPositive Partners Study:Serosorting and Superinfection

Goal: Determine the Risk of Systemic Superinfection AmongHIV-Positive, Seroconcordant Sexual Partnerships

Study Participants CalculationsViral

Sequencing

Positive Partners study:

a prospective cohort of

HIV-infected,

seroconcordant sexual

partnerships in San

Francisco

390 participants were

recruited, 329 eligible

(baseline virus

sequencing available)

Frequency of possible

exposure to

superinfection

(frequency and type of

sex, condom use)

Done at

baseline and

follow-up

Adapted from Larry Bragg. AIDS 2008; abstract MOPE0404.

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Mean Time of Positive HIV Status 9.9 Years

Participants Infected for More Than One Year Prior to Enrollment 287 (87%)

Participants Infected for More Than 10 Years Prior to Enrollment 146 (44.4%)

Episodes Unprotected Intercourse Per Year ≈77


Positive Partners StudyPositive Partners Study

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Summary of Sexual Exposure to Highly Divergent HIV VariantsSummary of Sexual Exposure to Highly Divergent HIV Variants


*UI = unprotected intercourse

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Positive Partners Study: ResultsPositive Partners Study: Results

• 233 infected individuals were followed prospectively during a total of 221 person-years.

• No evidence of superinfection occurred among participants.


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Incidence of Expected Superinfection in Individuals in the Absence of Mechanisms Blocking Superinfection

Incidence of Expected Superinfection in Individuals in the Absence of Mechanisms Blocking Superinfection


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46Incidence of Expected Superinfection in Individuals With Partner’s Viral Load> 1,500 Copies/mL in the Absence ofMechanisms Blocking Superinfection

Incidence of Expected Superinfection in Individuals With Partner’s Viral Load> 1,500 Copies/mL in the Absence ofMechanisms Blocking Superinfection


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Positive Partners Study: DiscussionPositive Partners Study: Discussion

Is unprotected sex “safe” for seroconcordant couples?

• Superinfection appears to be rare in patients with chronic

HIV infection.

• Mechanisms blocking superinfection may include viral

interference, antiviral immune responses or ART effects.

• Transmission of STIs, viral hepatitis (B/C) and human

papillomavirus needs to considered.

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Presentation SummaryPresentation Summary

HIV incidence is higher than previously expected, using new technology developed by the CDC.1

The burden of HIV is higher among certain groups, such as men who have sex with men of all races, African Americans and Hispanic Americans.

In addition to behavioral and structural efforts, there are exciting efforts underway to reduce HIV transmission through the use of antiretroviral therapy both as pre-exposure prophylaxis and post-exposure prophylaxis.

The use of antiviral treatment for the suppression of herpes simplex did not appear to have an effect in reducing HIV transmission in two large, randomized, controlled trials that were presented at AIDS 2008.2,3

Whether HIV-infected patients on effective antiretroviral treatment can forgo condoms has been a subject of much debate and more research is needed in this area.

Lastly, there appears to be no increased risk of HIV superinfection among seroconcordant HIV-infected couples with long-term infections.

It is clear that we have a long way to go with prevention efforts. The solution is unlikely to be found in any one strategy, but will need to be a combined approach of behavioral, structural and bio-medical interventions.

1H. Irene Hall et al. JAMA. 2008;300:520-529. 2Deborah Watson-Jones et al. AIDS 2008; abstract THAC0304. 3Connie Celum et al. AIDS 2008; abstract THAC0302.

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• This presentation was created to accompany The Body PRO's summaries of key research presented at AIDS 2008, by Anita Radix, M.D., M.P.H.

• The Body PRO's extensive coverage of AIDS 2008 also includes:– Summaries and analyses of research on a wide array of clinical

subjects.– Interviews with top researchers discussing the results of noteworthy

studies.– Audio podcasts you can play online or download to your computer or

MP3 player.– Narrated, online slide presentations highlighting major study results.

• Visit TheBodyPRO.com/AIDS2008 today for a full listing of our conference coverage!

the body pro the hiv resource for health professionals faculty: anita radix, m.d., m.p.h. associate...

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