Natural History of HIV Infection and Response to Antiretroviral Treatment in Women The Body PRO...

Natural History of HIV Infection andResponse to Antiretroviral

Treatment in Women

The Body PRO Coverage of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2008)

February 3-6, 2008Boston, Mass.

Faculty:Kathryn Anastos, M.D.Cal Cohen, M.D., M.S.David Wohl, M.D.

Kathryn Anastos, M.D.

Natural History of HIV Infection and Response to Antiretroviral Treatment in Women: A Summary of Key CROI 2008 Research

CROI 2008:Coverage From

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Kathryn Anastos, M.D.Kathryn Anastos, M.D., is the Executive Co-Director for Clinical and Scientific Programs of WE-ACTx (Women's Equity in Access to Care and Treatment, a community-based organization committed to providing HIV primary care, including antiretroviral therapy, to female survivors of genocidal rape in Rwanda. She has also developed and serves as the Principal Investigator of the Rwandan Women's Cohort Study (RWISA), funded by the U.S. National Institutes of Health (NIH). She is currently Professor of Medicine, Epidemiology and Population Health at Albert Einstein College of Medicine, Bronx, N.Y. Additionally, since 1993, Dr. Anastos has served as the Principal Investigator for the New York City/Bronx Consortium of the Women's Interagency HIV Study (WIHS), also funded by NIH.

Cal Cohen, M.D., M.S.Dr. Cal Cohen is the research director of Harvard Vanguard Medical Associates and Community Research Initiative of New England in Boston, Mass. He is also a clinical instructor at Harvard Medical School. In addition, he works as an HIV clinical management consultant and internist at Harvard Pilgrim Health Care. Dr. Cohen holds appointments at Brigham and Women's Hospital and Beth Israel Hospital, both in Boston, Mass. In addition to caring for HIV-infected patients and directing clinical research at a large HIV community-based research site, Dr. Cohen is actively involved in evaluating new antiretroviral therapies, the durability and longevity of the benefits from such therapies and issues regarding compliance and adherence. Dr. Cohen has served as a consultant to or has received honoraria or research support from Abbott Laboratories, Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline and Tibotec.

David Wohl, M.D. Dr. Wohl is an associate professor of medicine at the University of North Carolina at Chapel Hill, and co-directs HIV services for the North Carolina Department of Corrections. Dr. Wohl is an investigator in the NIAID-sponsored AIDS Clinical Trials Group (ACTG) and a member of the ACTG Complications of HIV Disease Research Agenda Committee. His research focuses on metabolic and infectious complications of HIV and its therapies, as well as issues related to medication adherence and access to care—particularly among incarcerated inmates with HIV infection. Dr. Wohl has served as a consultant to or has received honoraria or research support from Abbott Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck & Co, Roche Laboratories and Tibotec.

This activity is supported by an educational grant from

Faculty


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About This Slide Presentation

• This presentation was created to accompany The Body PRO's summary of key research presented at CROI 2008, featuring reports by Kathryn Anastos, M.D., Cal Cohen, M.D., M.S., and David Wohl, M.D. For more information about this program, please visit us on the Web at: TheBodyPRO.com/CROI2008

• Please feel free to use this slide presentation for personal reference or for your own presentations; however, we ask that you not modify any aspects of the slides contained within this presentation, so proper attribution can be retained. If you would like to publish all or part of this presentation, or repost any of these slides online, permission must first be obtained from Body Health Resources Corporation.

• Our gratitude goes out to all the researchers who granted permission for their slides to be adapted for this presentation.


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Natural History of HIV Infection and Response to Antiretroviral Treatment

in Women


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Regression Model Adjusted for Race, Country and History of AIDS

Adapted from Beatriz Grinsztejn et al. CROI 2008; abstract 672.

-0.05

0.00

0.05

0.10

0.15

0.20

0.25

50 100 150 200 250

Exact Screening CD4+ Lymphocytes (mm3)

Mal

e-F

em

ale

Mea

n V

ira

l L

oad

D

iffe

ren

ce (

Lo

g1

0 C

op

ies/

mL

)


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Cox Proportional Hazards Model of Factors at Enrollment Associated With Death Among HIV-Infected Persons Attending the CCC in Nashville, Tenn.a

Diana Lemly et al. CROI 2008; abstract 810. Reprinted with permission.

Variable Univariate HR (P Value)

HR (95% CI) P Value

Black Race 1.61 (< 0.001) 1.34 (1.02 – 1.75) 0.035

Female Sex 1.11 (0.47) 1.54 (1.13 – 2.09) 0.006

Known IVDU 1.73 (0.001) 1.65 (1.19 – 2.29) 0.003

AIDS Diagnosis Prior to First Visit

2.57 (< 0.001) 1.46 (1.05 – 2.03) 0.02

Age at First Visit, Years 1.04 (< 0.001) 1.03 (1.02 – 1.05) < 0.001

Baseline CD4+ Lymphocyte Count

0.997 (< 0.001) 0.998 (0.997 – 0.999) < 0.001

aIn addition to the variables listed, the following variables were included in the multivariate model: ART/HAART exposure prior to first visit, baseline CD4+ percent, baseline HIV-1 RNA level. These variables were not significantly associated with death.


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Cox Proportional Hazards Model of Factors, Including HAART Utilization, Associated With Deatha

aIn addition to the variables listed, the following variables were included in the multivariate model: ART/HAART exposure prior to first visit, baseline CD4+ percent, baseline HIV-1 RNA level and ART exposure prior to initiation of HAART. These variables were not significantly associated with death.bUnivariate HR 0.45 (P < 0.001)

Variable HR (95% CI) P Value

> 65% of time in care on HAARTb 0.20 (0.15 – 0.27) < 0.001

Black Race 1.04 (0.78 – 1.37) 0.81

Female Sex 1.52 (1.12 – 2.07) 0.007

Known IVDU 1.36 (0.98 – 1.89) 0.07

AIDS Diagnosis Prior to First Visit 1.82 (1.30 – 2.54) < 0.001

Age at First Visit, Years 1.04 (1.03 – 1.06) < 0.001

Baseline CD4+ Lymphocyte Count, Cells/mm3 0.997 (0.997 – 0.998) < 0.001

Diana Lemly et al. CROI 2008; abstract 810. Reprinted with permission.


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Comparison of Factors 12 Months After HAART Between African and European Americans

TotalAfrican

AmericansEuropean Americans

P-Value(AA vs. EA)

Viral Load (VL)

VL < 400 c/ml (%) 61.6 55.7 67.9 < 0.001

VL Change From Start – 12 Months Post-HAART (Log10)

-1.6 ± 1.3 -1.4 ± 1.3 -1.7 ± 1.4 < 0.001

HAART Regimen at 12 Months (%) 0.980

No Change From Start 54.0 54.3 53.8

Change - Different HAART 34.4 34.2 34.6

Change - Not on HAART 11.6 11.5 11.6

Amy Weintrob et al. CROI 2008; abstract 809. Reprinted with permission.


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Univariate and Multivariate Predictors of CD4+ Change From Pre-ART to Longest Follow-Up (n = 400)

Kathryn Anastos et al. CROI 2008; abstract 667. Reprinted with permission.


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Univariate and Multivariate Predictors of Change in HIV-1 RNA From Pre-ART to Longest Follow-Up (n = 229)

Kathryn Anastos et al. CROI 2008; abstract 667. Reprinted with permission.


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Distribution of the Underlying Causes of Death in HIV-Infected Adults, According to Their Gender

0

10

20

30

40

50

60

AIDS Cancer Cardio HCV Non-AIDS-DefiningInfection

0

10

20

30

40

50

60

AIDS Cancer Cardio HCV Non-AIDS-DefiningInfection

2000n = 964

2005n = 1042

Men Women

Adapted from Mojgan Hessamfar-Bonarek et al. CROI 2008; abstract 666.


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Longer Cumulative Exposure to NRTIs Was Associated With Greater IR in HIV-Infected Women

Estimated Relative Difference in Medians† (95% CI)

No. Person-Visits Median HOMA Unadjusted Analyses Adjusted Analysis‡

Cumulative number of NRTI-years

0 1,910 2.07 1 (reference) 1 (reference)

> 0 to 3.0 3,039 2.25 1.06 (0.99, 1.13) 1.06 (0.98, 1.16)

> 3.0 3,032 2.22 1.09 (1.01, 1.19) 1.13 (1.02, 1.25)

Cumulative number of PI-years


> 0 to 1.5 1,837 2.22 1.07 (1.01, 1.14) 1.03 (0.96, 1.10)

> 1.5 1,835 2.25 1.06 (0.98, 1.13) 1.01 (0.93, 1.10)

Cumulative number of NNRTI-years


> 0 to 1.0 1,699 2.17 0.99 (0.93, 1.06) 0.96 (0.89, 1.03)

> 1.0 1,696 2.20 1.00 (0.93, 1.08) 0.95 (0.86, 1.03)*1,614 HIV-infected women contributed a total of 7,981 person-visits of follow-up including the index visit†Anti-log of coefficient of exposure group from regression model ‡Adjusted for cumulative number of NRTI, PI, or NNRTI reported from WIHS baseline through the visit prior to index, WIHS cohort status (1994-1995 or 2001-2002), race, baseline HCV antibody status, family history of diabetes, and age, smoking status, BMI, CD4 count, menopause assessed at visit immediately prior to index; if data for a particular variable was missing at visit immediately prior to index then data concurrent with index visit was used; 1,482 women contributing 7,529 person-visits were included in analysis

Phyllis Tien et al. CROI 2008; abstract 933. Reprinted with permission.


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Sex Differences Between Regimens for Time to Virologic Failure and Time to Treatment Limiting Toxicity

Male Female

Regimen HR 95% CI P HR 95% CI P

Time to Virologic Failure

EFV vs. LPV 0.61 0.41 – 0.90 0.01 0.78 0.42 – 1.48 0.43

EFV vs. LPV/EFV 0.76 0.51 – 1.13 0.18 1.35 0.62 – 2.93 0.46

LPV vs. LPV/EFV 1.16 0.81 – 1.66 0.42 2.01 1.0 – 4.0 0.05

Time to Toxicity

EFV vs. LPV 1.0 0.62 – 1.62 0.99 1.31 0.52 – 3.22 0.56

EFV vs. LPV/EFV 0.83 0.53 – 1.31 0.43 3.48 0.93 – 13.1 0.07

LPV vs. LPV/EFV 0.85 0.54 – 1.36 0.50 3.86 1.04 – 14.4 0.04

Adapted from Sharon Riddler et al. CROI 2008; abstract 776.


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Immune Markers

Adjusting for CD4 cell

count Adjusting for

HIV RNA

(n=225)

(n=225) OR 95% CI P-value OR 95% CI P-value CD8+CD38+DR-

<32 1.00

1.00 >32 0.82 (0.52, 1.31) 0.41 0.83 (0.53, 1.30) 0.41 CD8+CD38+DR+

<34 1.00

1.00 >34 1.94 (1.01, 3.75) 0.047 1.68 (0.92, 3.06) 0.09 CD8+CD38-DR-

<17 1.00

1.00 >17 0.53 (0.28, 1.00) 0.050 0.63 (0.31, 1.27) 0.19 CD8+CD38-DR+

<7 1.00

1.00 >7 0.61 (0.38, 0.98) 0.041 0.71 (0.42, 1.19) 0.19 CD4+CD38+DR-

<49 1.00

1.00 >49 1.51 (0.95, 2.38) 0.08 1.24 (0.77, 1.98) 0.38 CD4+CD38+DR+

<10 1.00

1.00 >10 1.72 (1.01, 2.94) 0.0470 1.66 (0.97, 2.83) 0.06 CD4+CD38-DR-

<28 1.00

1.00 >28 0.48 (0.29, 0.79) 0.004 0.51 (0.30, 0.87) 0.013 CD4+CD38-DR+

<6 1.00

1.00 >6 0.77 (0.49, 1.20) 0.24 0.92 (0.60, 1.42) 0.71

Multivariate* Association of Immune Markers With HIV-1 Genital Shedding

LaShonda Spencer et al. CROI 2008: abstract 674. Reprinted with permission.

*Adjusted for ARV therapy, genital infection and CD4+ or HIV viral load.


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Prevention of HIV Transmission to Women


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Effect of Vaginal Flora on CVL HIV RNA:Cross-Sectional Analysis – Adjusted for Log10 Plasma HIV RNA

Jane Hitti et al. CROI 2008; abstract 27LB. Reprinted with permission.


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H2O2+ Lactobacillus Acquisition/Loss:Effect on Log10 CVL HIV RNA

Jane Hitti et al. CROI 2008; abstract 27LB. Reprinted with permission.


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Male Circumcision and HSV-2 Acquisition Over a 24 Month Follow-Up

0 2 4 6 8 10 12 14 16 18

Age 20 to 24

InconsistentCondom Use

2+ SexualPartners

Overall

Incidence (%)

Circumcision

Control

RR 0.76P = 0.019

CI 0.50 to 0.96

RR 0.72P = 0.07

CI 0.50 to 1.03

RR 0.53P = 0.001

CI 0.35 to 0.78

RR 0.63P = 0.015

CI 0.44 to 0.91

In almost all sociodemographic and behavioral subgroups, the relative risk of HSV-2 incidence was lower in the circumcision arm.

Adapted from Aaron Tobian et al. CROI 2008; abstract 28LB.


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Vaginal Infections at 12 Month Follow-Up By Husband’s Study Arm

Adapted from Aaron Tobian et al. CROI 2008; abstract 28LB.

0 10 20 30 40 50

BV

Severe BV

Trichomonas

Prevalence (%)

Circumcision

Control

There was a significant reduction of progression from normal flora to BV and reduced persistence of BV from enrollment to follow-up in wives of circumcised men.

PRR 0.53CI 0.33 to 0.85

PRR 0.31CI 0.18 to 0.54

PRR 0.80CI 0.71 to 0.89


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Male-to-Female HIV Transmission by Study Arm for Wives Concurrently Enrolled With Their Partner: Intent-to-Treat Analysis

0 to 24 Months

Control

Incidence/100 Person Years

9.1

Transmission/Person Year

8/88

Intervention

Incidence/100 Person Years

14.4

Transmission/Person Year

17/118

IRR (95% CI)

1.59 (0.7 – 4.3)

Adapted from Maria J. Wawer et al. CROI 2008; abstract 33LB.

Includes one crossover in control arm and eight crossover men in MC arm.


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Male-to-Female Transmission by Timing of Wound Healing and Resumption of Sex, 0 to 6 Month Follow-Up Interval

Timing of Resumption of SexEarly vs. Later Resumption

of Sex

Sex Before Wound Healing Was Complete

Sex At or After Wound Healing

Intervention Arm

Transmitted/n 5/18 6/63 RR = 2.92 (1.01 – 8.46)

P = 0.06Percentage 27.8 9.5

Control Arm: Transmitted/n = 6/68 Percentage = 8.8

Excludes uncircumcised men (8) and couples who did not resume sex (3)

Adapted from Maria J. Wawer et al. CROI 2008; abstract 33LB.


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HIV Acquisition Events and Rate Per 100 Person-Years by Gender

Total Acyclovir Placebo

nRate/100

person-yearsn

Rate/100 person-years

nRate/100

person-years

Total 139 3.6 75 3.9 64 3.3

Men 67 3.2 31 3.0 36 3.4

Womena 72 4.0 44 4.9 28 3.1

aExcluding time off study drug use due to pregnancy. HIV incidence for acyclovir was 3.8/100 person-years and for placebo 3.3/100 person-years. Overall Hazard Ratio: 1.13 (95% CI 0.81 to 1.59).

Overall Hazard Ratio: 1.16 (95% CI 0.83 to 1.62)

Adapted from Connie Celum et al. CROI 2008; abstract 32.


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Pharmacokinetic Results

Julie Dumond et al. CROI 2008; abstract 135LB. Reprinted with permission.


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DMPA and HIV Acquisition

Elizabeth Stringer. CROI 2008; abstract 94. Reprinted with permission.


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OCPs and HIV Acquisition



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Other Studies of HIV Disease Progression and HC



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Epithelial Disruption

Intact genital tract mucosal epithelium is impervious to HIV

Disrupted epithelium allows HIV to migrate across the barrier and infect target cells

Mucosalepithelium

T-cells

HIV-1

Disruptive microbicide (N-9)

Betsy Herold et al. CROI 2008: abstract 26. Reprinted with permission.

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