"Central Hypertension"‚ in China: Towards the nation-wide use of SphygmoCor t...
HIV Transmission in Women: What we Know, Where are the Gaps
1.
2. HIV Transmission in Women: What
we Know, Where are the Gaps
Susan Cu-Uvin, MD
Professor Ob-Gyn and Medicine
Alpert School of Medicine, Brown University
3. Objectives
• HIV epidemiology in women globally and
locally
• Identify risk factors for HIV transmission
• Modalities to reduce HIV transmission to and
from women
• Where are the gaps
6. Global Fact Sheet
Adults and children living with HIV 36 700 000 [34 000 000 - 39 800 000]
Adults aged 15 and over living with HIV 34 900 000 [32 400 000 - 37 900 000]
Women aged 15 and over living with HIV 17 800 000 [16 400 000 - 19 400 000]
Men aged 15 and over living with HIV 17 200 000 [15 900 000 - 18 600 000]
Children aged 0 to 14 living with HIV 1 800 000 [1 500 000 - 2 000 000]
Adult aged 15 to 49 HIV prevalence rate 0.8 [0.7 - 0.9]
HIV Prevalence among young men (15-24) 0.3 [0.2 - 0.5]
HIV Prevalence among young women (15-24) 0.4 [0.4 - 0.5]
Adults and children newly infected with HIV 2 100 000 [1 800 000 - 2 400 000]
Adults aged 15 and over newly infected with HIV 1 900 000 [1 700 000 - 2 200 000]
Women aged 15 and over newly infected with HIV 900 000 [800 000 - 1 000 000]
Men aged 15 and over newly infected with HIV 1 000 000 [900 000 - 1 200 000]
Children aged 0 to 14 newly infected with HIV 150 000 [110 000 - 190 000]
Adult aged 15 to 49 HIV Incidence rate 0.05 [0.04 - 0.06]
12. Diagnoses of HIV Infection among Adult and Adolescent Females, by
Race/Ethnicity, 2010–2014
United States and 6 Dependent Areas
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically
adjusted to account for reporting delays, but not for incomplete reporting.
a Hispanics/Latinos can be of any race.
13. Diagnoses of HIV Infection and Population among Adult and
Adolescent Females, by Race/Ethnicity 2014—United States
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been
statistically adjusted to account for reporting delays, but not for incomplete reporting.
a Hispanics/Latinos can be of any race.
14. Diagnoses of HIV Infection among Adult and Adolescent Females,
by Region and Race/Ethnicity
2014—United States
Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.
a Hispanics/Latinos can be of any race.
15. Diagnoses of HIV Infection among Adult and Adolescent
Females, by Race/Ethnicity and Transmission Category
2014—United States and 6 Dependent Areas
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically
adjusted to account for reporting delays and missing transmission category, but not for incomplete reporting.
a Hispanics/Latinos can be of any race.
b Heterosexual contact with a person known to have, or to be at high risk for, HIV infection.
c Includes blood transfusion, perinatal exposure, and risk factor not reported or not identified.
26. GT HIV Shedding Among Women with PVL
<80 copies/mL
Genital Tract HIV-1 RNA Shedding Patterns:
46 women with PVL <80 copies/mL
n %
Non-shedder 22 48%
Shedder 24 52%
• Indeterminate 12 26%
• Intermittent 8 17%
• Persistent 4 8%
Among the 9 women with total hysterectomy, one woman had persistent
shedding pattern. The others were non-shedders.
30. Resistant HIV-1 Mutants
• 11 HIV(+) women failing therapy and 4 drug
naïve women
• PVL ranged from 11,000-1,100,000 copies/ml
• CVL ranged from 400-28,000 copies/ml
• 5/7 women failing therapy had resistant mutations
in CVL not found in blood (protease codon
46,54,82,84,90; RT codon 184)
• 2/7 women failing therapy had same sequences as
in blood
• 4/4 drug naïve women showed no resistance in
CVL or plasma
31.
32.
33. High Discordance in Blood and Genital Tract HIV-1 Drug Resistance in Indian
Women
Failing 1st-Line Therapy
• Examine plasma and genital tract viral load (PVL; GVL) and compare drug
resistance concordance in plasma, genital tract and peripheral blood
mononuclear cells (PBMCs) in HIV-1 infected South Indian women, under the
hypothesis of existing inter-compartmental discordances.
• We performed PVL testing of adult women at YRG CARE, Chennai, India, on
first-line antiretroviral therapy for >6 months; GVL in women with PVL>2,000
copies/mL; and plasma, genital and PBMC reverse transcriptase genotyping in
women with GVL>2,000 copies/mL.
• Of 200 women enrolled, 62 (31%) had PVL>1,000 copies/mL (WHO threshold).
Of 42/54 (78%) women with PVL>2000 copies/mL, 31/42 (74%) had detectable
GVL
• Women with high PVL had higher GVL
• Paired plasma-genital sequences (95% subtype C) were available for 21
women; mean age 34 years, median treatment duration of 33 months, median
CD4 of 217 cells/μL, median PVL of 5.4 log10copies/mL, median GVL of 4.6
log10copies/mL. PBMC sequences were available for 20/21(95%) women.
• Any resistance in plasma, genital tract and PBMCs was seen in 91%, 91% and
90%, respectively; 76%, 66% and 75% with dual-class resistance.
34. High Discordance in Blood and Genital Tract HIV-1 Drug
Resistance in Indian Women
Failing 1st-Line Therapy
• Complete concordance in all three compartments was seen in only 10%
women, 24% plasma-genital tract, 35% plasma-PBMCs and 15% genital
tract-PBMCs
• Odds of genital tract- PBMCs discordance were significantly larger than
plasma-PBMCs. Discordant mutations detected in genital tract or PBMC
but not in plasma led to clinically-relevant higher predicted resistance in
33% and 45% of women, respectively.
• We identified fair, not perfect, PVL-GVL concordance and high inter-
compartmental drug resistance discordance among south-Indian women
failing first-line antiretroviral therapy
• Such discordances might lead to unrecognized drug resistance
transmission and re-emergence, compromising treatment outcomes,
particularly relevant to countries like India, where sexual transmission is
the major mode of HIV infection.
36. Compartmentalization Between
Blood and Genital Tract
• Differences in viral load levels
• Differences in diversity, divergence, and
evolution of virus
• Differences in viral subpopulations
• Differences in resistance patterns
• Differences in co-receptor usages
37. Coinfection with STDs/BV and HIV
Shedding in Genital Secretions
• Several reports of increased HIV-1 RNA and HIV-
1DNA in the genital tract in the presence of STDs
( gonorrhea, chlamydia, trichomoniasis, HSV-2,
genital ulcer diseases), cervical inflammation,
candida vaginitis, bacterial vaginosis
• Meta-analysis ( Rotchford et al): 48 studies
• Gonorrhea: HIV detected in 41% vs 32% without
GC (p=0.004)
• Treatment of STD in women decreased HIV
detection from 39% to 29%
38. Probability of HIV infection in
the HIV- partner
per 10 000 contacts
HIV plasma RNA in the
HIV+ partner (copies/ml) HSV+ HSV-
<1700 10 0.4
1700-12,499 23 5
12,500-38,499 18 2
>38,500 36 7
Source: Wawer M et al, Lancet 1999
HSV control: Rationale for HSV-2 control
to reduce HIV transmission
39. Reduction of HIV-1 RNA levels with Therapy to
Suppress Herpes Simplex Virus
(Nagot et al, NEJM 2007)
• Randomized double-blind, placebo controlled trial
of HSV suppresive therapy with Valacyclovir
(500mg 2x a day), Burkina Faso, 140 HIV(+) and
HSV-2 (+) women, not on ART
• 24 weeks follow up; 12 wks before and 12 wks
after randomization
• Valacyclovir therapy was significantly associated
with decrease in frequency of genital HIV-1 RNA
(OR 0.41, 95%CI 0.21-0.80) and reduced mean
PVL by 0.53log10 (95%CI,-0.72—0.35)
44. Reproductive Hormones and HIV
Acquisition
Reproductive hormones influence
susceptibility to HIV infection in human
ectocervical and vaginal tissues by altering
thickness of epithelial layer and disrupting
tight junction proteins between epithelial cells
43
45. Cohort Status N Hormonal supplementation that will be started after enrollment
A Premenopausal N=20 None
B Premenopausal N=20 Depomedroxyprogesterone acetate- DMPA
C Premenopausal N=30 Hormonal Oral Contraceptive Pills (OCP)
D Postmenopausa
l
N=20 Estrogen vaginal cream
46. Baseline Screening → Study Enrollment→ Monthly specimencollection
Menstrual Calendar 1. cervical and vaginal biopsy
2. endocervical cytobrush
Weekly telephone 3. cervicovaginal lavage
monitoring by study nurse 4. peripheral blood (20 cc)
47. CONTROL HIV
EFFECT OF HIV ON INTEGRITY AND THE ORGANIZATION OF THE
ECTOCERVICAL EPITHELIAL LAYER
E: Epithelium; L: Lumen of ectocervix. Magnification-10x.
CONCLUSION: Exposure to HIV-1 for 24 hrs. did not alter the integrity and the organization of the
ectocervical epithelial layer.
46
48. SUBMUCOSA
SUBMUCOSASUBMUCOSA
SUBMUCOSA
CONTROL SUPERNATANT HIV ISOTYPE CONTROL
ZO1/DAPICLAUDIN1/DAPI
EFFECT OF HIV ON TIGHT JUNCTION PROTEIN ZO-1, CLAUDIN-1 IN
ECTOCERVICAL TISSUES
n=3
Blue: DAPI nuclear staining
Red: ZO1 and Claudin 1 staining
ZO-1 EXPRESSION
47
49. SUBMUCOSA
SUBMUCOSA
SUBMUCOSA
CLAUDIN4/DAPIE-CADHERIN/DAPI
CONTROL SUPERNATANT HIV ISOTYPE CONTROL
EFFECT OF HIV ON TIGHT JUNCTION PROTEIN (CLAUDIN-4) AND ADHERENS
JUNCTION (E-CADHERIN) IN ECTOCERVICAL TISSUES
n=3
n=3
Blue: DAPI nuclear staining
Green: Claudin 4 and Ecadherin staining
CLAUDIN-4 EXPRESSION
E-CADHERIN EXPRESSION
48
50. CONTROL
HIV
(DAPI nuclear staining (Blue), ZO-1 staining (red). n=3
CONCLUSION: Exposure to HIV-1 does not cause significant changes in tight junction and
adherens junction proteins in ectocervical epithelium
EFFECT OF HIV ON ZO-1 PROTEINS IN ECTOCERVICAL TISSUES
SUBMUCOSA
SUBMUCOSA
49
51. No difference in the levels of Na/K/AtPase expression between
HIV-exposed and control tissues
(Sankapal el at AIDS 2016)
52. HIV p24 (in pg/ml) production in ectocervical tissues obtained from different phases
of menstrual cycle.
-10000
-5000
0
5000
10000
15000
20000
25000
Day
4
Day
8
day
12
day
16
HIVP24pg/ml
ECTOCERVICAL TISSUES
Proliferative
phase
average
ovulatory
phase
secretory
phase
51
CONCLUSION: Susceptibility to HIV infection in ectocervical/vaginal tissues was
not significantly different at different phases of menstrual cycle.
53. CONCLUSION:
TJ/AJ protein expression in ectocervical tissues does not change significantly over the
course of menstrual cycle with/without HIV
p=0.42p=0.32
p=0.43
n=3n=3 n=3
p=0.28p=0.21 p=0.33
n=3
n=3 n=3
ECTOCERVICAL TISSUES
TIGHT JUNCTION PROTEIN AND ADHERENS JUNCTION IN ECTOCERVICAL TISUES AT
DIFFERENT STAGES OF MENSTURAL CYCLE
HIV EXPOSED ECTOCERVICAL TISSUES
52
54. Reduced levels of genital tract immune biomarkers in
postmenopausal women: implications for HIV acquisition
Mariel Jais, PharmD; Naji Younes, PhD; Stacey Chapman, RN; Susan Cu-Uvin, MD; Mimi Ghosh, PhD (AJOG 2016)
55. Reduced levels of genital tract immune biomarkers in
postmenopausal women: implications for HIV acquisition
Mariel Jais, PharmD; Naji Younes, PhD; Stacey Chapman, RN; Susan Cu-Uvin, MD; Mimi Ghosh, PhD (AJOG 2016)
56. The impact of pregnancy on anti-HIV activity of
cervicovaginal secretions
Brenna L. Hughes, MD, MSc; Riana Dutt, ScB; Christina Raker, ScD; Melody Barthelemy, MBA;
Richard M. Rossoll, MD; Bharat Ramratnam, MD; Charles R. Wira, MD; Susan Cu-Uvin, MD (AJOG 2016)
57. HIV-1 Reservoir Dynamics in the Female Reproductive
Tract
The Known Unknowns
• The exact relationship between blood and tissue
reservoirs
• The nature of reservoirs in female reproductive tract
• Decay, maintenance, and mechanisms of persistence
• Role of inflammation and hormonal fluctuations
• The response of tissue reservoirs to virus reactivation
strategies
• The impact of tissue drug levels on virus evolution
58. Longitudinal Study of FRT HIV-1 Reservoirs
Goal: determine the relationship between blood and female
reproductive tract tissue HIV reservoirs
1)Is the the HIV tissue reservoir of the female reproductive tract
is fundamentally different in its biology from the better-
characterized circulating peripheral blood reservoir?
2)Do measures of HIV persistence in the female genital tract
provide novel insights into testable virus eradication strategies,
relative to similar analyses performed in plasma and PBMC?
59.
60.
61.
62.
63.
64. Prevention Modalities
Condoms PEP Voluntary Male
Circumcision
Needle ExchangeVaccine
Abstinence
Microbicides HIV & STI Testing STI Treatment
HIV Treatment
Harm Reduction
PrEP
65. Murnane et al, CROI 2013, Abstract #1000
Summary of Oral PrEP Efficacy Data
66. Relationship Between Effectiveness
and Adherence in Microbicide & PrEP
Trials
Pearson correlation = 0.86, p=0.003
Pearson correlation = 0.86, p=0.003
-60
-40
-20
0
20
40
60
80
100
0 10 20 30 40 50 60 70 80 90
Effectiveness(%)
Percentage of Participants’ Samples with detectable drug levels
(Analysis based on a subset of total trail participants, Pearson correlation = 0.86, p=0.003)
CAPRISA 004
iPrEX
TDF2
PartnersPrep (TDF)
PartnersPreP (FTC)
FemPrEP
VOICE (TDF)
VOICE (Truvada)
VOICE (TFV gel)
SS Abdool Karim, personal communication
Partners PrEP (TDF)
Partners PrEP (Truvada)
67. An Early Phase 1, Single Center Study to
Assess the Safety of MB66, a Combined Anti-
HIV (VRC01-N) and Anti-HSV
(HSV8-N) Monoclonal Antibody Film for
Vaginal Application as Microbicide (MB66-01)
Susan Cu-Uvin, MD
Kenneth Mayer, MD
Thomas Moench, MD
Kathleen Morrow, PhD
Karen Tashima, MD
68. Study Product
• Biologic Name: VRCO1-N monoclonal antibody
HSV8-N monoclonal antibody
• Dosage Form: Vaginal film (2” x 2” square; 0.002” thickness,
mass 0.2 gm) 10 mg each monoclonal antibody per film
69. *Assumes STIs diagnosed and treated in both partners
PrEP for Pregnancy: Scenarios
17.0% 24.1% 29.3% 30.3%
p < 0.0001
p < 0.0001
p < 0.0001 p < 0.0001
26.9% 28.3% 29.1% 29.2%17.8% 23.1% 26.8% 27.3%
71. Research to Implementation:
MTCT in Resource-Rich Countries Over Time
1993: 1994: 1997: 1999: 2001: 2002: 2003: 2006:
WITS PACTG PACTG WITS PACTG PACTG WITS UK
076 185 247 316
AZT
Era
Combination
ARV Era
75. Summary
• High prevalence of HIV among young women in SSA
• US: African-American women are at the highest risk of having
HIV
• Several biological factors affect risk of HIV acquisition (PVL, GT
VL, STIs, ART, hormonal contraception…)
• Compartmentalization of blood and GT viral load
• Prevention Methods: microbicides, PrEP
• Success in decreasing mother to child transmission with cART
in HIV infected pregnant women
• Gaps: precise mode of transmission, sustained remission
(cure), vaccine, better microbicides, HIV and aging women
76. Brown University All the women who participated in the studies
Susan Cu-Uvin
Bharat Ramratnam
Stacey Chapman
Timothy P. Flanigan Northwestern University
Kenneth Mayer (Harvard) Richard D’Aquila
Charles CJ Carpenter
Joseph Hogan Pittsburgh University
Brenna Hughes Phalguni Gupta
Angela Caliendo Soni Sankapal
Lab team
Dartmouth Harvard CFAR
Charles Wira Athe Tsibris and lab staff
John Fahey
Mimi Ghosh (GWU)