ВИЧ-инфекция у женщин : стратегии 3 ключевых глобальных проблем.2016.HIV Infection Among Women- Strategies to Address 3 Key Global Challenges .2016

HIV Infection Among Women:
Strategies to Address 3 Key
Global Challenges
Supported by an independent educational grant from
ViiV Healthcare

Slide credit: clinicaloptions.com
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Faculty
Linda-Gail Bekker, MBChB, DTMH, DCH,
FCP(SA), PhD
Chief Operating Officer
Desmond Tutu HIV Foundation
Deputy Director
Desmond Tutu HIV Centre
President Elect
International AIDS Society
Faculty of Health Sciences
University of Cape Town
Cape Town, South Africa
Wafaa M. El-Sadr, MD, MPH, MPA
Director
ICAP at Columbia University
Director
Global Health Initiative
Professor of Epidemiology and Medicine
Columbia University
New York, New York
Catherine Hankins, MD, PhD, FRCPC,
CM
Scientific Chair, INTEREST 2016
Amsterdam Institute for Global Health and
Development
Department of Global Health
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands
Honorary Professor
London School of Hygiene and Tropical
Medicine
London, United Kingdom
Nelly Mugo, MBChB, MMed, MPH
Head, Sexual Reproductive Adolescent
Child Health Research Program
Centre for Clinical Research
Kenya Medical Research Institute (KEMRI)
Nairobi, Kenya

Disclosures
Linda-Gail Bekker, MBChB, DTMH, DCH, FCP(SA), PhD, has
disclosed that she has received consulting fees or fees for non-CME/CE
services from Janssen, Merck, and Merck Sharp & Dohme and has
received funds for research support (paid to her institution) from Alere,
Gilead Sciences, and ViiV Healthcare.
Wafaa M. El-Sadr, MD, MPH, MPA, has no real or apparent conflicts of
interest to report.
Catherine Hankins, MD, PhD, FRCPC, CM, has disclosed that she has
received fees for non-CME/CE services from Gilead Sciences.
Nelly Mugo, MBChB, MMed, MPH, has disclosed that she has received
funds for research support from Merck.

Agenda
 Program Overview
– Bringing Optimal Regimens to Women in Resource-
Constrained Settings
– Delivering ART to All Women Who Will Benefit
– Reducing New Infections Among Young Women and
Adolescent Girls

Disproportionate HIV Burden Among
Young Women
Slide credit: clinicaloptions.comUNAIDS. Global AIDS update. 2016.
New HIV Infections Among Adults, Global Adult Population, Global
New HIV Infections Among Adults,
Sub-Saharan Africa Adult Population, Sub-Saharan Africa
Female
Male27%
≥ 25
yrs old
20%
15-24 yrs of age 14%
15-24 yrs of age
39%
≥ 25
yrs old
39%
≥ 25
yrs old
11%
15-24 yrs of age
11%
15-24 yrs of
age
39%
≥ 25
yrs old
31%
≥ 25
yrs old
25%
15-24
yrs old
12%
15-24 yrs of age
31%
≥ 25
yrs old
33%
≥ 25
yrs old
17%
15-24 yrs of age
17%
15-24 yrs of age
32%
≥ 25
yrs old

8
South Africa[1]
1. HIV Prevalence by Age Group: SA Incidence &
Behavioural Survey 2012. Human Sciences Research Council.
2. National AIDS and STI Control Programme (NASCOP). Kenya AIDS
Indicator Survey 2012: Final Report. Slide credit: clinicaloptions.com
Disproportionate HIV Burden in Females
by Age Group
Kenya[2]
36
31.6
2828.4
17.4
5.6
0.7 5.1
17.3
25.6
28.8
15.8
13.4 15.5
14.8
9.7
4.6
2.4
5.5
40
32
24
16
8
0
Females
Males
Females
Males
19.7
6
4
2
0
15 16 17 18 19 20 21 22 23 24
Age (Yrs)Age (Yrs)
HIVPrevalence(%)
HIVPrevalence(%)

Bringing Optimal Regimens to
Women in Resource-
Constrained Settings

Studies of ART in Women and in
Global Populations Are Needed
 Interactions of ART with
steroid hormones/
contraception
 Safety of ART in
pregnancy
 Differences between
women and men in
– Physiology
– Weight distribution
– Pharmacodynamics
– Body dysmorphia
 Geographic and
practice/site differences
 Interactions of ART with
tuberculosis drugs

Fewer Data on ART in Women and in
Global Populations
 Historically, most ART trials conducted in high-income countries
and in men
– Most decision making for ART in women is extrapolated from these
data
 Women constituted 19.2% of participants in systematic review of
ART trials[1]
– Likely owing to entry criteria requiring birth control and precluding
pregnancy and breast-feeding
– Limited improvement in inclusion of women from 2001-2004 (18.2%)
to 2008-2011 (21.6%)[1]
 Phase III data emerging from studies of modern ART regimens in
women: GRACE,[2] WAVES,[3] ARIA[4]
Slide credit: clinicaloptions.comReferences in slidenotes.

GRACE: DRV/RTV + Background Regimen
in Treatment-Experienced Pts
 North American, open-label phase IIIb trial evaluating sex-
based differences in efficacy and safety (N = 429)
– 67% of participants were women; 84% of participants were black
or Hispanic
 Specific measures are needed to retain HIV-positive women in
clinical trials
Wk 48 Outcome, % Women Men P Value
Virologic response
 By ITT analysis
 Excluding pts who withdrew*
50.9
73.0
58.5
73.5
.067
.44
Discontinuations 32.8 23.2 .042
*For reasons other than virologic failure.
Currier J, et al. Ann Intern Med. 2010;153:349-357.

WAVES: EVG/COBI/TDF/FTC vs ATV + RTV +
TDF/FTC in Treatment-Naive Women
 International, randomized, controlled, double-blind phase III trial
– In EVG/COBI/TDF/FTC and ATV + RTV + TDF/FTC arms, 49% and 47%
of pts were black with median ages of 34 and 35 yrs, respectively
EVG/COBI/TDF/FTC QD +
Placebos for ATV, RTV, and TDF/FTC QD
(n = 289)
ATV + RTV + TDF/FTC QD +
Placebo for EVG/COBI/TDF/FTC QD
(n = 286)
Women
with HIV-1 RNA
≥ 500 copies/mL,
no previous ART,
and eGFR ≥ 70 mL/min
(N = 575)
Wk 48
Open-label
extension
ATV 300 mg; RTV 100 mg; TDF/FTC 300/200 mg; EVG/COBI/TDF/FTC 150/150/300/200 mg
Squires K, et al. Lancet HIV. 2016;[Epub ahead of print].
Squires K, et al. IAS 2015. Abstract MOLBPE08.
Stratified by
HIV-1 RNA
and race

WAVES: EVG/COBI/TDF/FTC Superior to
ATV + RTV + TDF/FTC At Wk 48
 Overall tx difference: 6.5%
(95% CI: 0.4% to 12.6%)
 No significant differences
in changes in eGFR, spine
or hip BMD, LDL-c or
HDL-c, TC:HDL ratio, or
TGs
 Significantly greater
increase in TC with
EVG/COBI
 Fewer discontinuations
due to AEs with
EVG/COBI (5 vs 19)
Wk48HIV-1RNA<50c/mL(%)
100
80
60
40
20
0
Overall ≤ 100,000 > 100,000
HIV-1 RNA (copies/mL)
EVG/COBI/TDF/FTC ATV + RTV + TDF/FTC
87
81
86
82
90
78
n = 289 286 220 214 69 72
Emergent Resistance,
n
EVG/COBI/TDF/FTC
(n = 289)
ATV+RTV+TDF/FTC
(n = 286)
Final resistance analysis
population
7 12
Developed resistance
mutations to study drugs
0 3
Squires K, et al. Lancet HIV. 2016;[Epub ahead of print].
Squires K, et al. IAS 2015. Abstract MOLBPE08.

Study 104/111: EVG/COBI/FTC/TAF vs
EVG/COBI/FTC/TDF in Tx-Naive Women
 Wk 48 results of phase III studies in North America, EU, Asia,
Latin America
‒ In women, at Wk 48 EVG/COBI/FTC/TAF associated with
numerically less spine and hip BMD loss, significantly less decline
in eGFR, numerically greater decline in proteinuria
Orkin C, et al. EACS 2015. Abstract 798. Slide credit: clinicaloptions.com
EVG/COBI/FTC/TAF EVG/COBI/FTC/TDF
100
80
60
40
20
0
95
87
92 91
n = 126 111 674 673
Women Men
0 4 8 12 16
0.2
7.9
15.6
Favors TAFFavors TDF
Treatment Difference in Women
(95% CI)
-16 -12 -8 -4

SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC
in Tx-Naive Men and Women
 Results of phase III study of 833 pts, 16% of whom were
women
Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;70:515-519. Slide credit: clinicaloptions.com
Efficacy driven by fewer discontinuations due to adverse events in the DTG +
ABC/3TC arm (3%) vs EFV/TDF/FTC arm (11%)
DTG + ABC/3TC EFV/TDF/FTC
100
80
60
40
20
0
88
81
Wk 48
71
63
Wk 144
0 4 8 12 16
2.0
8.3
14.6
Favors
DTG + ABC/3TC
Favors
EFV/TDF/FTC
Wk 144 Treatment Difference
(95% CI)
-16 -12 -8 -4

ARIA: DTG/ABC/3TC vs ATV + RTV +
TDF/FTC in Treatment-Naive Women
 Randomized, open-label phase IIIb trial in women in
North America, European Union, Argentina, Puerto
Rico, Russian Federation, South Africa, Thailand
– Primary endpoint: Wk 48 HIV-1 RNA < 50 copies/mL
Orrell C, et al. AIDS 2016. Abstract THAB0205LB. Slide credit: clinicaloptions.com
DTG/ABC/3TC QD
(n = 248)
ATV + RTV + TDF/FTC QD
(n = 247)
Women
with HIV-1 RNA
≥ 500 copies/mL,
no previous ART,
HLA-B*5701 negative,
and CrCl ≥ 50 mL/min
(N = 495)
Wk 48
ATV 300 mg, RTV 100 mg, TDF/FTC 300/200 mg, DTG/ABC/3TC 50/600/300 mg
Women
who became
pregnant offered
option to enter
DTG/ABC/3TC
pregnancy study
NCT02075593

ARIA: DTG/ABC/3TC Superior to ATV +
RTV + TDF/FTC at Wk 48
DTG/ABC/3TC ATV + RTV + TDF/FTC
100
80
60
40
20
0
82
71
Overall
0 4 8 12 16
3.1
10.5
17.8
Favors
DTG/ABC/3TC
Favors ATV +
RTV + TDF/FTC
Treatment Difference (95% CI)
 Superior efficacy driven by fewer discontinuations due to AEs and fewer
virologic failures
Outcome, %
DTG/ABC/3TC
(n = 248)
ATV+RTV+TDF/FTC
(n = 247)
Discontinuations due to AEs 4 7
Virologic failure 6 14
Orrell C, et al. AIDS 2016. Abstract THAB0205LB.
20-20 -16 -12 -8 -4

Global Guideline
Recommendations

Discrepancies in Current International
Guidelines for Treatment-Naive Pts
Regimen IAS-USA[1] SA NDOH[2] WHO[3]
EFV/TDF/FTC
RPV/(TDF or TAF)/FTC
NVP + TDF/FTC
(EFV or NVP) + ZDV + 3TC
LPV/RTV + TDF/FTC
DRV/(COBI or RTV) + (TDF or
TAF)/FTC or + ABC/3TC
DTG/ABC/3TC
DTG + (TDF or TAF)/FTC
EVG/COBI/(TDF or TAF)/FTC
RAL + (TDF or TAF)/FTC
Preferred/recommended Alternative Not listed
1. Günthard HF, et al. JAMA. 2016;316:191-210.
2. South African Guidelines. 2015. 3. WHO Guidelines. June 2016. Slide credit: clinicaloptions.com

WHO Recommendations: First-line ART
 Prefer fixed-dose combinations and once-daily regimens
Bold denotes recommendations in pregnant or breast-feeding women
*For adults and adolescents, discontinue first-line use of d4T.
†ABC or boosted PIs (ATV/RTV, DRV/RTV, LPV/RTV) can be used in special circumstances.
‡In adolescents, ABC can be substituted for TDF in alternative combinations.
§No safety and efficacy in pregnant women, HIV/TB coinfection, and adolescents 12 yrs of age or younger.
‖In adolescents, conditional recommendation, moderate-quality evidence.
¶EFV at lower dose (400 mg/day).
WHO Guidelines. June 2016.
Preferred Combination Alternative Combinations*†
NNRTI NRTIs NNRTI or INSTI NRTIs
EFV TDF + 3TC (or FTC)
EFV (or NVP) ZDV + 3TC
NVP TDF‡ + 3TC (or FTC)
DTG§‖ or EFV
400 mg§‖¶ TDF‡ + 3TC (or FTC)

Global Guideline
Recommendations:
Pregnancy and Contraception

WHO Recommendations: ART in Pregnant
or Breastfeeding Women
 DHHS: EFV can be used after first 8 wks of
pregnancy[2]
Preferred Combination[1] Alternative Combinations[1]
NNRTI NRTIs NNRTI NRTIs
EFV TDF + 3TC (or FTC)
EFV (or NVP) AZT + 3TC
NVP TDF + 3TC (or FTC)
1. WHO Guidelines. June 2016. 2. DHHS Guidelines. July 2016.

What ARVs Are Compatible With
Contraception?
 Several PIs, EFV, and EVG/COBI-based regimens have
drug interactions with combined oral contraceptives
– Decrease or increase in blood levels of ethinyl estradiol,
norethindrone, or norgestimate could potentially
– Decrease contraceptive efficacy
– Increase estrogen- or progestin-related adverse events (eg,
thromboembolism)
 Women receiving ARVs with significant interactions with
hormonal contraceptives should use an additional or
alternative contraceptive, consider ARV switch
Slide credit: clinicaloptions.comDHHS Guidelines. July 2016.

Drug Interactions Between Hormonal
Contraceptives and ARVs
Slide credit: clinicaloptions.comWHO Guidelines. June 2016.
Hormonal
Contraceptive
NRTI PI NNRTI INSTI
Any* ATV LPV DRV RTV EFV NVP ETR RPV DTG RAL EVG/c
Combined oral
contraceptives
Etonogestrel or
levonorgestrel
implant
Transdermal
ethinyl estradiol
Norethisterone
(norethindrone)
DMPA
injectable
No clinically significant interaction or interaction unlikely
Potential interaction that may require monitoring or regimen alteration
*Includes 3TC, ABC, ddI, d4T, FTC, TDF, ZDV.

Weighing the Options: Key Considerations
 Efficacy/safety and guidelines
 Compatibility with contraception
 Compatibility with pregnancy
 Simplicity of regimen (especially if head of household,
if family includes children who are HIV positive, etc)
 PMTCT
 Availability of data in women

Delivering ART to All Women
Who Will Benefit

Global Scale-up of HIV Treatment
Global AIDS Response Progress Reporting (UNAIDS/UNICEF/WHO) and
UNAIDS/WHO estimates. Slide credit: clinicaloptions.com
16 million
PeoplereceivingART
14 million
12 million
10 million
8 million
6 million
4 million
2 million
0 million
2.2 million
690,000
7.5 million
14.9 million
African region
Region of the Americas
Southeast Asia region
European region
Western Pacific region
Eastern Mediterranean region
15.8 million

START: Immediate vs Deferred Therapy
for Asymptomatic, ART-Naive Pts
Primary Endpoint Immediate ART Deferred ART
No. with event (%) 42 (1.8) 96 (4.1)
Rate/100 PY 0.60 1.38
HR (immediate/deferred) 0.43 (95% CI: 0.30-0.62; P < .001)
 57% reduced risk of
serious events or death
with immediate ART
 68% of primary endpoints
occurred in pts with
CD4+ cell counts > 500
cells/mm3
10
8
6
4
2
0
CumulativePercent
WithEvent
0 6 12 18 24 30 36 42 48 54 60
Mos
INSIGHT START Study Group. N Engl J Med. 2015;373:795-807.
Lundgren J, et al. IAS 2015. Abstract MOSY0302.
2.5
5.3
Immediate ART
ART deferred until
CD4+ cell count
≤ 350 cells/mm3,
AIDS, or event
requiring ART

START: Serious Events or Death
 72% reduced risk of serious AIDS events with
immediate ART
 39% reduced risk of serious non-AIDS events with
immediate ART
INSIGHT START Study Group. N Engl J Med. 2015;373:795-807.
Lundgren J, et al. IAS 2015. Abstract MOSY0302. Slide credit: clinicaloptions.com
Endpoint, n Immediate ART
(n = 2326)
Deferred ART
(n = 2359)
HR (Immediate/Deferred)
Serious AIDS
events
14 50 0.28 (95% CI: 0.15-0.50; P < .001)
Serious non-
AIDS events
29 47 0.61 (95% CI: 0.38-0.97; P = .04)
Cancer 14 39 0.36 (95% CI: 0.19-0.66; P = .001)
Death 12 21 0.58 (95% CI: 0.28-1.17; P = .13)

HPTN 052: ART for Prevention of HIV
Transmission in Serodiscordant Couples
 ART offered to all index
pts in delayed ART arm
from May 2011 after
interim results
– 84% of pts in delayed
ART arm had initiated
ART at Yr 1 and 98%
prior to study closure
 No linked HIV transmissions observed when index
participant stably suppressed on ART
Cohen MS, et al. IAS 2015. Abstract MOAC0101LB.
Safren SA, et al. J Acquir Immune Defic Syndr. 2015;69:234-240.
Partner
Infections, n
(Rate/100 PY)
Overall
(April 2005 - May 2015)
Early
(4314 PY F/U)
Delayed
(4180 PY F/U)
All 19 (0.44) 59 (1.41)
Linked 3 (0.07) 43 (1.03)
Risk Reduction
With Early ART, %
All infections 69 --
Linked infections 93 --

ART Recommendations for HIV Infection
 WHO[1] and DHHS[2] guidelines recommend ART
for all HIV-positive people worldwide, regardless
of CD4+ cell count
1. WHO Guidelines. June 2016.
2. DHHS Guidelines. July 2016.

June 2016: “Treat All” Uptake in Adults
and Adolescents
Slide credit: clinicaloptions.comSource: WHO Map Production, 2016.
Treat all
Recommending treat all later in 2016
CD4 ≤ 500 cells/mm3
CD4 ≤ 350 cells/mm3
Data not reported
Fast track countries
High income countries
Not applicable

June 2016: Global Adoption of Option B+
 Option B+: All HIV-infected pregnant women offered
lifelong ART, regardless of CD4+ cell count
Slide credit: clinicaloptions.comSource: WHO Map Production, 2016.
Option B+
Option B
Option A
Data not reported Fast track countries
High income countries
Not applicable

Rapid Increase in ART Coverage During
Pregnancy With Option B+ in Malawi
Gupta SK, et al. CROI 2016. Abstract 789. Slide credit: clinicaloptions.com
ARTInitiations
ARTCoverage(%)
10,000
8000
6000
4000
2000
0
100
80
60
40
20
0
Option B+
ART initiations
among pregnant
women
ART initiations
among breast-
feeding women
ART coverage at
final ANC visit

Lower Retention With Option B+ vs With
ART for Eligible Women in Malawi
 Women initiating ART during pregnancy were more likely to have no
follow-up visit and more likely to be lost to follow-up during the first 2
yrs vs women staring ART for advanced HIV disease
Women Starting ART During
Pregnancy (Option B+)
Women Starting ART for WHO Stage 3/4
Disease or CD4+ Cell Count < 350 cell/mm3
Haas AD, et al. Lancet HIV. 2016:3;e175-e182. Slide credit: clinicaloptions.com
Mos From ART Initiation Mos From ART Initiation
0 6 12 18 24 30 36
CumulativeIncidence(%)
Alive on ART
Dead
Stopped ART
Lost to follow-up
No follow-up
0 6 12 18 24 30 36
CumulativeIncidence(%)
Alive on ART
Dead
Stopped ART
Lost to follow-up
No follow-up
100
60
40
20
0
80
100
60
40
20
0
80

 Randomized trial in Argentina, Botswana, Brazil, China, Haiti,
Peru, Thailand, and United States of women receiving ART
(74% LPV/RTV, 19% ATV/RTV) or stopping ART following
pregnancy
PROMISE: Continuing vs Stopping ART in
Postpartum, Non–Breast-feeding Women
Currier J, et al. AIDS 2016. Abstract THAB0103LB.
Continue ART
(n = 827)
Stop ART*
(n = 825)
HIV-infected, ART-naive (except PMTCT)
postpartum women without guideline-
specified indication for ART, CD4+ cell
count ≥ 400 cells/mm3, not breast-feeding
(N = 1652)
Randomized within
42 days of delivery
*Restarted ART if CD4+ cell count fell < 350 cells/mm3 or was clearly indicated.
Current analysis reflects median follow-up of 2.31 yrs for Continue ART arm and 2.35 yrs for Stop ART arm.
Pts seen 4 wks post enrollment,
then every 12 wks through 84 wks
after last enrollment

PROMISE: Efficacy and Safety at Median
Follow-up of Approximately 2 Yrs
 Between treatment arms, no significant difference in primary
safety or efficacy endpoints
– Time to first grade 3/4 sign or symptom or grade 2-4 chemistry or
hematology result (P = .08)
– Time to AIDS-defining event, serious non-AIDS event, or any-
cause death (P = .54)
 Secondary endpoints: continuing ART associated with lower
HIV event rate
Currier J, et al. AIDS 2016. Abstract THAB0103LB.
Outcome, n (Rate/100 PY) Continue ART (n = 827) Stop ART (n = 825) HR (95% CI)
Composite of HIV/AIDS-related
or WHO stage 2/3 events
57 (3.09) 99 (5.49) 0.56 (0.41-0.78)
WHO stage 2/3 events 39 (2.02) 80 (4.36) 0.47 (0.32-0.68)

HIV Care Continuum
Test
Adherence and
Viral Suppression
Initiate
ART
El-Sadr, PEPFAR Meeting, February 2016
HIV PositivePopulation HIV Treatment Undetectable
Viral Load
General, KP, PP
Retain, Counsel,
Monitor & Support
Adherence
Support

UNAIDS: 90-90-90 Treatment Targets
Target 1:
90% of HIV+
people
diagnosed
Target 2:
90% of
diagnosed
people on ART
Target 3:
90% of people on
ART with HIV-1
RNA suppression
Slide credit: clinicaloptions.comLevi J, et al. IAS 2015. Abstract MOAD0102.
100
80
60
40
20
0
HIV-Positive
People
Diagnosed On ART Viral
Suppression
People(%)
90%
81%
73%
36.9
million
33.2
million
29.5
million
26.9
million
n =

UNAIDS: 90-90-90 Global Estimated Gaps
100
80
60
40
20
0
HIV-Positive
People
Diagnosed On ART Viral
Suppression
Breakpoint 1:
13.4 million
undiagnosed Breakpoint 2:
14.9 million
not treated
Breakpoint 3:
15.3 million
not virally
suppressed
53%
41%
32%
People(%)
Slide credit: clinicaloptions.comLevi J, et al. IAS 2015. Abstract MOAD0102.
Target 1:
90% of HIV+
people
diagnosed
Target 2:
90% of
diagnosed
people on ART
Target 3:
90% of people on
ART with HIV-1
RNA suppression
36.9
million
19.8
million
15.0
million
11.6
million
n =

90-90-90 Gaps: US and Puerto Rico
Slide credit: clinicaloptions.comCDC. HIV Care Continuum for the United States and Puerto Rico.
 Data on persons living with HIV (N = 1,218,400)
100
80
60
40
0
People(%)
20
87.2
39.1 36.2
30.2
Diagnosed Received
Medical Care
On ART Viral
Suppression

90-90-90 Gaps: Swaziland
Birx DL for PEPFAR. 11th International Conference on HIV Treatment and
Prevention Adherence. May 2016.
Men Women
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
People(n)
HIV
Positive
Diagnosed On
ART
Viral
Suppression
PEPFAR Target 2016 PEPFAR Target 2017 90-90-90
93,716
52,004
(55%)
84,344
49,641
(53%)
75,910
43,684
(47%)
68,319 80,556
(60%)
97,106
94,771
(71%)
107,895
99,283
(75%)
119,884133,204
HIV
Positive
Diagnosed On
ART
Viral
Suppression

Challenges in Delivering the Promise of
ART
Challenge Underlying Causes
Unaware of HIV status
 Unware of individual risk for HIV
 Fear of stigma and discrimination
 Limited access to HIV testing
 Provider practice of risk-based vs routine screening
Late diagnosis of HIV
disease
 HIV testing not accessible or underutilized
 Providers and individuals unaware of HIV symptoms or risk
Late initiation of ART
 Limited access to care services
 Barriers (eg, poverty, substance abuse, homelessness, mental illness)
 Stigma (eg, racial/ethnic, sex)
 Mistrust of the healthcare system
 Unaware of importance of HIV care
Failure of HIV positives to
link to care
 Limited access to treatment
 Limited treatment literacy and fear of adverse events
 Provider attitudes regarding ART initiation for some pts
Inability to achieve/
maintain viral suppression
 Limited access to effective antiretroviral treatment
 Barriers to adherence (eg, mental illness, poverty, homelessness)
 Limited availability of adherence support
Slide credit: clinicaloptions.comEl-Sadr WM, et al. J Acquir Immune Defic Syndr. 2010;55:S116-S121.

Reducing New Infections
Among Young Women
and Adolescent Girls

Compared With Males, Females Have a
Higher Risk of HIV Infection per Sex Act
 High mucosal exposure
– Large cervical-vaginal mucosal surface area
– Semen can stay in vagina for up to 3 days
 High levels of activated immune cells in female genital
tract and increased expression of HIV receptor
 Microabrasions during coitus
 Men delay diagnosis and treatment and often have
higher HIV-1 RNA than women

Females With Fewer Sex Partners Are
More Likely to Acquire HIV Than Males
National AIDS and STI Control Programme (NASCOP). Kenya AIDS
Indicator Survey 2012: Final Report. Slide credit: clinicaloptions.com
0 1 2-3
0.91.0
4.6
1.2
8.1
2.9
40
30
20
10
0
HIVPrevalence(%)
Women
Men
4-5 6-9 10+ Don’t
knowNumber of Lifetime Sexual Partners
13.4
5.8
18.0
7.5
26.1
6.1
11.9
10.1
 Survey of women and men in Kenya aged 15-64 yrs (N = 13,720)

Biological Vulnerabilities of Young Women
 Compared with older women, young women have
higher HIV vulnerability[1]
– Immature cervix with large ectopy[2]
 Pregnancy doubles the risk for HIV acquisition[3]
 More women acquire HSV-2 than men[4]
– HSV-2 infection increases risk for HIV infection 3-fold[5]
1. UNAIDS. The gap report. 2014.
2. Kleppa E, et al. Sex Transm Infect. 2015;91:124-129.
3. Mugo NR, et al. AIDS. 2011;25:1887-1895.
4. Rajagopal S, et al. Open Forum Infect Dis. 2014;1:ofu043.
5. Freeman EE, et al. AIDS. 2006;20:73-83.

High STI Prevalence Among Young
Women in Sub-Saharan African Trials
 Clinical trials enrolling young African women with access
to monthly counseling/testing (ASPIRE,[1] VOICE,[2]
FEMPrEP,[3] FACTS 001,[4] CAPRISA 004[5])
– HIV incidence across placebo arms: 4.0-9.1/100 PY
STI Prevalence, %
Chlamydia trachomatis 12-14
Neisseria gonorrhoeae 3-6
Trichomonas vaginalis 6-7
Treponema pallidum (syphilis) 1-2
1. Baeten JM, et al. N Engl J Med. 2016;[Epub ahead of print].
2. Marrazzo JM, et al. N Engl J Med. 2015;372:509-518.
3. Van Damme L, et al. N Engl J Med. 2012;367:411-422.
4. Rees H, et al. CROI 2015. Abstract 26LB.
5. Abdool Karim Q, et al. Science. 2010;329:1168-1174.

 Sexual coercion is commonly reported by young
women[1]
– In a South African study, 48% of girls aged 14-16 yrs
had a coerced first sexual encounter[2]
Structural and Behavioral Vulnerabilities
of Young Women and Adolescent Girls
1. Birdthistle I, et al. AIDS Behav. 2013;17:2430-2438.
2. Maharaj P, et al. J Biosoc Sci. 2007;39:231-244.

 Early sexual debut increases HIV risk for girls[1]
 Delay in sexual debut associated with higher likelihood of
condom use[2]
Impact of Sexual Debut
10
8
6
4
2
0
< 15 ≥ 15
Age at Sexual Debut (Yrs)
Total
5.3
0.3
3.5
1.5
4.0
1.2
Women
Men
HIVPrevalence(%)
HIV Prevalence Among Young Women and Men Aged 15-24 Yrs by
Age of Sexual Debut in Kenya
1. Pilgrim NA, et al. Vulnerable Child Youth Stud. 2014;9:193-205.
2. National AIDS and STI Control Programme (NASCOP). Kenya AIDS
Indicator Survey 2012: Final Report.

Phylogenetic Linkages in South Africa
Suggest Triangle of HIV Infection
 Sexual networks identified by sequencing HIV viruses (N =
1589) and examining phylogenetically linked clusters
Slide credit: clinicaloptions.comde Oliveira T, et al. AIDS 2016. Abstract TUSS0603.
Men aged 25-40 yrs, n = 79
(HIV prevalence 40.3%)
Women aged younger
than 25 yrs, n = 43
Women aged
25-40 yrs, n = 56
Mean age
difference:
1.1 yrs
Mean age
difference:
8.7 yrs
39% of the men
linked to a woman
aged younger than
25 yrs are also linked
to a woman aged
25-40 yrs

Which Interventions Are
Applicable and Evidence Based?

Impact of Education and Youth Centers for
Adolescent Girls and Young Women
 Education attainment associated with lower risk for
acquiring HIV[1]
 Sex education and HIV education programs can
reduce risk behaviors[2] but no evidence of impact on
HIV incidence
– Community randomized trial of teacher-led, peer-
assisted sex education in primary schools in Tanzania[3]
 Youth centers have low evidence of impact, serve a
limited population, and do not reach vulnerable
youth[4,5]
1. Jukes M, et al. AIDS. 2008;22:S41-S56. 2. Kirby DB, et al. J Adolesc
Health. 2007;40:206-217. 3. Doyle AM, et al. PLoS Med. 2010;7:
e1000287. 4. Zuurmond MA, et al. Stud Fam Plann. 2012;43:239-254.
5. Chandra-Mouli V, et al. Glob Health Sci Pract. 2015;3:333-340.

Interventions in Young Women: Impact of
Cash Transfers Alone
 Variation on impact of cash transfer may be related to
difference in geography and population and an indicator that
interventions should not be the same for all young women[7]
Country Intervention Outcome
South Africa[1] Cash transfer Decreased unsafe partner selection
Kenya[2] Cash transfer Delayed sexual debut
Tanzania (RESPECT)[3] Cash transfer Reduced STI prevalence
Lesotho[4] Lottery tickets Reduced HIV incidence
Malawi (SIHR)[5] Cash transfer
Reduced HIV and HSV-2 prevalence
(but no effect in school dropouts)
South Africa (HPTN068)[6] Cash transfer No difference in HIV acquisition
1. Cluver L, et al. Lancet Glob Health. 2013;1:e362-e370. 2. Handa S, et
al. PLoS One. 2014;9:e85473. 3. de Walque, et al. BMJ Open.
2012;2:e000747. 4. Björkman-Nyqvist M, et al. IAS 2013. Abstract
TUPDC0106. 5. Baird SJ, et al. Lancet. 2012;379:1320-1329. 6. Pettifor
A, et al. AIDS Behav. 2016;[Epub ahead of print]. 7. Pettifor A, et al. AIDS
Behav. 2012;16:1729-1738.

Biological Interventions and
Ongoing Studies

2016 WHO Guidance Recommends PrEP
for Wider Range of Populations
 New guidance recommends considering PrEP for
anyone at substantial risk of HIV infection (ie, HIV
incidence > 3/100 PY without PrEP)
– Based on individual assessment and local evidence
rather than limiting to specific populations or risk groups
 Adolescent girls at substantial risk of HIV in sub-
Saharan Africa are a priority population for PrEP
Slide credit: clinicaloptions.comWHO Guidelines. June 2016.

PrEP Is Effective Among Young Women
 In meta-analysis of 18 studies, adherence was a significant
moderator of PrEP effectiveness[1]
– Low adherence diminished effectiveness of PrEP among young
populations
– Age and sex did not moderate PrEP effectiveness
 Studies establishing PrEP effectiveness included substantial
numbers of young women
‒ In TDF2, 45.7% of participants were women[2]
‒ In Partners PrEP subgroup analysis of women younger than
30 yrs of age, TDF was 77% and TDF/FTC 72% protective[3]
‒ In a VOICE subgroup analysis, women with detectable plasma
tenofovir had a 47% risk reduction for HIV infection[4]
Slide credit: clinicaloptions.comReferences in slidenotes

ASPIRE and IPM 027: PrEP With
Dapivirine Ring in Women in SSA
 Multicenter, randomized, double-blinded phase III trials of HIV-
negative women with primary endpoints of HIV incidence vs
placebo
 Adherence was lowest in women aged 21 yrs or younger
 HOPE (ASPIRE) and DREAM (IPM 027 Ring Study) programs
are implementing open-label extension dapivirine ring studies
1. Baeten JM, et al. N Engl J Med. 2016;[Epub ahead of print].
2. Nel A, et al. CROI 2016. Abstract 110LB.
HIV Protection Efficacy
vs Placebo, %
ASPIRE[1]
(N = 2629)
IPM 027 Ring Study[2]
(N = 1959)
Overall 27
(95% CI: 1 to 46, P = .05)
30.7
(95% CI: 0.90 to 51.5, P = .04)
Age > 21 yrs 56
(95% CI: 31 to 71, P < .001)
NA

MTN-020/ASPIRE Subcohort: Dapivirine
Vaginal Ring
 Multicenter, double-blind, placebo-controlled randomized phase
III trial
 Subcohort analysis evaluating residual dapivirine levels and HIV
acquisition suggests adherence predicts HIV protection
 Additional analysis accounting for length of ring use suggests
dose-response relationship between adherence and HIV
protection
Brown E, et al. AIDS 2016. Abstract TUAC0105LB.
Outcome Placebo Nonadherent
(≥ 23.5 mg DAP*)
Low/High
Adherence
(< 23.5 mg DAP*)
Medium/High
Adherence
(< 22 mg DAP*)
Infections, n 50 13 14 7
HIV incidence/100 PY 4.6 3.6 1.9 1.5
Risk reduction vs PBO,
% (95% CI; P value)
--
31
(-28 to 63; .24)
56
(20 to 76; .007)
65
(22 to 84; .01)
*Residual levels of DAP remaining in returned rings.

PrEP: Ongoing Studies
 Oral PrEP
– 9 demonstration studies in young women in Africa
 Injectable PrEP
Study Population/Setting Design
HPTN
076
Low-risk women in South Africa,
Zimbabwe, and the United States
TMC278LA vs
placebo
HPTN
083
MSM and transgender women
in Africa, Asia, and the Americas
Cabotegravir vs
TDF/FTC

HPTN 069/ACTG A5305: Maraviroc-
Containing PrEP in US Women
 Prospective, double-blind, placebo-controlled phase II trial
powered to estimate safety/tolerability, not efficacy
– First randomized interventional HIV PrEP study for US
women
Gulick R, et al. AIDS 2016. Abstract TUAC0102.
Maraviroc 300 mg QD†
(n = 47)
Maraviroc 300 mg + FTC 200 mg QD†
(n = 47)
HIV-uninfected
adults born female
at risk of HIV
infection,*
CrCl ≥ 70 mL/min,
HBsAg negative,
no IV drug use
(N = 188)
Wk 48
*Condomless vaginal or anal intercourse with ≥ 1 man with HIV infection or unknown HIV status within previous 90 days.
†Dosed with matching placebo for a total of 3 pills taken PO daily in each arm.
Maraviroc 300 mg + TDF 300 mg QD†
(n = 47)
TDF 300 mg + FTC 200 mg QD†
(n = 47)

HPTN 069/ACTG A5305: Safety and
Tolerability
 Across treatment arms, no significant differences in:
– Number of grade 3/4 AEs (P > .05)
– Proportion of discontinuations (P > .2)
– Time to permanent discontinuation (P = .2)
 35 (19%) pts with 48 grade 3/4 AEs (n = 11 considered treatment
related)
 36 (19%) d/c, mostly at pt request (n = 16) or for pregnancy (n = 9)
 No new on-study HIV infections, although analysis not powered to
evaluate efficacy
 Comparable plasma drug concentrations across regimens (P > .6)
with 60% to 65% adherence
Gulick R, et al. AIDS 2016. Abstract TUAC0102.

Evidence for Contraceptive Options and
HIV Outcomes (ECHO) Trial
 Open-label, randomized study comparing risk of HIV
infection with injectable depot medroxyprogesterone
acetate vs levonorgestrel implant vs copper IUD at 18
mos after enrollment
 Enrolling women in Kenya, South Africa, Swaziland,
and Zambia (N  7800)
 Results anticipated in 2018
Slide credit: clinicaloptions.comClinicalTrials.gov. NCT02550067.

Role of the Clinician
 To be effective, must be holistic and nonjudgmental
 Screen for structural and social vulnerability
 Address clinical needs
– Sexual and reproductive health
– STIs
– Psychosocial needs
– PrEP where applicable
– Youth-friendly services

Girls and Young Women: Multiple
Vulnerabilities, Multiple Interventions
 In adolescents: lack of evidence, further studies unlikely
Biomedical Behavioral Structural
HIV testing Abstinence Keep girls in school
Oral PrEP Reduce number of partners Prevent early marriage
Vaginal ring Delay age of sexual debut Empower girls, enhance gender equity
Treatment as
prevention
Reduce injection drug and
other substance abuse
Reduce transactional sex:
cash transfers programs
STI screening,
treatment
Improve legal structures:
sex work, protection of women
Male, female
condoms
Improve access to reproductive health
services (STI diagnosis/treatment)
Contraception Improve family stability,
poverty reduction
Increase food security

Conclusions
 Data on HIV treatment in women are emerging
 Treatment should take into account reproductive health
 New WHO guidelines and global 90-90-90 targets offer the
opportunity to achieve epidemic control
 Addressing gaps in the HIV care continuum will require
tailored interventions for the needs of women, with specific
attention to women enrolled in Option B+ programs
 Multicomponent strategies, including behavioral and
structural interventions, are needed to address high
incidence of HIV in women

Go Online for More CCO
Coverage of HIV!
Interactive Virtual Presentation featuring streaming narration of these
slides
Additional podcast on global challenges in HIV among women
clinicaloptions.com/hiv

ВИЧ-инфекция у женщин : стратегии 3 ключевых глобальных проблем.2016.HIV Infection Among Women- Strategies to Address 3 Key Global Challenges .2016

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