HIV Infection in Women
Judith S. Currier, MD
University of California, Los Angeles
1
Overview
Epidemiology
Natural History
Treatment Issues
2
Case 1
 42 year old woman presents to ER with seizure
 No past medical history
 Born in Los Angeles, no travel
 Works in Medical Records at local hospital
 Married, monogamous for 15 years, no children
 Physical exam within normal limits
 Labs WBC 2.7, hgb 9.8 plt 320
3
4
DDx includes brain abscess or malignancy
HIV testing discussed with patient
5
HIV Testing Recommended
 She reluctantly reports that her husband is
HIV +
He has been on treatment for past five years
She has never been tested
 She has been in good health without
symptoms ( recurrent leukopenia noted in
outpatient records)
 Her husband suggested that there was
nothing to do if she did not have any
symptoms…. And she believed him
6
Follow-up
HIV test positive,
CD4 =25 cells/mm3
Toxo IgG positive, Ig M negative
Starts on pyrimethamine/sulfadiazine and folinic
acid
Steroids tapered
Started on antiretroviral therapy and responds well
Why did this woman resist HIV testing for 10 years?
7
Impact ongoing access to diagnosis
and quality care
Stigma/fear of disclosure
Disempowerment
Caregivers for others
Domestic violence
Lack of health insurance
Co-morbidities
Cultural barriers
Poverty
8
Epidemiology
Global
US
Global summary of the AIDS epidemic 
2012
Number of people
living with HIV
Total
Adults
Women
Children (<15 years)
35.3 million [32.2 million – 38.8 million]
32.1 million [29.1 million – 35.3 million]
17.7 million [16.4 million – 19.3 mill]
3.3 million [3.0 million – 3.7 million]
People newly
infected
with HIV in 2012
Total
Adults
Children (<15 years)
2.3 million [1.9 million – 2.7 million]
2.0 million [1.7 million – 2.4 million]
260 000 [230 000 – 320 000]
AIDS deaths in 2012
Total
Adults
Children (<15 years)
1.6 million [1.4 million – 1.9 million]
1.4 million [1.2 million – 1.7 million]
210 000 [190 000 – 250 000]
30.1 Million HIV-Infected Adults World
Wide: 56% are Women
Global Total: 34
Million
Source: UNAIDS,2010
2007AIDS epidemic
update
2007AIDS epidemic
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2007AIDS epidemic
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Different Groups of Women Have
Their Own Needs and Issues
Female
adolescence
Pregnancy
WOMEN
Older
Women
32
Each Year, American Youth Experience
 Nearly 900,000 teen
pregnancies
 Approximately 9 million
new cases of STDs
 An estimated 15,000
new cases of HIV
among those aged 1524
U.S. Teenage Pregnancy Statistics, Alan Guttmacher Institute, 2004, and Weinstock, H.,
et al., Sexually Transmitted Diseases in American Youth 2000
33
Vulnerability of Female Youth to HIV
Sexually active female teenagers may be
biologically more susceptible to HIV acquisition than
older women
 Highest age-specific rates of both
gonorrhea and Chlamydia may increase
the relative risk of acquiring HIV 2-3 fold
 The less mature cervix commonly has
larger areas of cervical ectopy than that of
a more mature woman.
 Hopkins
Age-discrepant
sexual
relationships
report
34
Unique Issues of Adolescents
Not still children – not yet adults
Increasingly earlier onset and physical changes of
puberty
 Age at menarche: 16.9 years in 1800 vs. 12.8 in
2000
Cognitive development – transition to abstract
reasoning
Continuing development of gender identity
Biological/social factors make adolescents
vulnerable to unsafe sexual practices
35
Older Women
69 yr old Hispanic woman undergoing colposcopy
Resident performing procedure sustains a needlestick
Requests HIV testing on the patient
The patient tests positive
Her husband died of TB seven years earlier
She had never been offered HIV testing and was not
aware of his HIV
CD4 was 92 cells/mm3
Viral load 45,000
36
How Many Women Age 65-74 Years
Report Having Sexual Intercourse in
Prior Year ?
A. 10%
B. 25%
C. 40%
D. 70%
E. My grandmother has sex?
37
Sex is Not Only for the Young
Percentage reporting sex
in last 12 months
100
80
Women
61.6
60
39.5
40
16.7
20
0
57-64
65-74
75-85
Age
Lindau NEJM 2007 357(8):762-774 National Social Life, Health, and Aging Project (NSHAP), 2004
38
Age is Not a Condom
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Sex is Not Only for the Young
100
Men
Percentage reporting sex
in last 12 months
83.7
80
61.6
Women
67.0
60
39.5
40
38.5
16.7
20
0
57-64
65-74
75-85
Age
Lindau NEJM 2007 357(8):762-774 National Social Life, Health, and Aging Project (NSHAP), 2004
40
US Population with HIV is Aging
160,000
160,000
140,000
140,000
120,000
120,000
100,000
100,000
80,000
80,000
60,000
60,000
40,000
40,000
20,000
20,000
0
0
Age group
Age group
US 2007
Median age: 40-44 years
28.6% ≥ 50 years
US 2008
Median age: 45-49 years
30.6% ≥ 50 years
Brooks JT et al. Am J Pub Health 2012 Aug;102(8):1516-1526
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
US Population with HIV is Aging
160,000
160,000
140,000
140,000
120,000
120,000
100,000
100,000
80,000
80,000
60,000
60,000
40,000
40,000
20,000
20,000
0
0
Age group
Age group
US 2007
US 2008
With 1.5% increase annually, Median age: 45-49 years
Median age: 40-44 years
by28.6%
2020
≥ 5050%
years> age 50
30.6% ≥ 50 years
11% of new HIV infections annually in the US occur
among persons over the age
ofet al.50
Brooks JT
Am J Pub Health 2012 Aug;102(8):1516-1526
www.aids2012.org
Washington D.C., USA, 22-27 July 2012
Why are older patients getting
infected?
1) Individual lack of awareness of HIV risk factors
 Many older people are newly single
 Poor understanding of their risk for a disease
 Perceive as disease affecting young or gay people
 Perceived risk decreased even among high risk groups
1. Levy et al. JAIDS 2003 33(Supp 2): S59-67.
2. Savasta et al., J Assoc Nurses AIDS Care 2005 15(1): 50-59.
43
Why are older patients getting
infected?
2) Altered biological risk for HIV acquisition
 Women: changes related to menopause
 No risk for pregnancy  risk compensation
- Decreased need for condoms as birth control
• Cervicovaginal changes favoring infection
- ↓ estrogen → thinner epithelium, less mucous
- risk of microabrasions
- Immune system changes
- ↑ CCR5+CD4+ T-cells (target for wild type virus)
- ↑ pro inflammatory factors (↑ HIV replication)
1. Meditz et al., 2011 Conference on Retroviruses and Opportunistic infection, abstract #33
2. Rollenhangen and Asin, Conference on Retroviruses and Opportunistic infection, abstract #776
44
Why are older patients getting
infected?
Condom use is rare among persons age > 50 years
National Survey of Sexual Health and Behavior (early 2009)
 20% used a condom for any vaginal/anal sex
Among respondents self-identified as single with >1 sex partner in last 12 months
Used a condom during last vaginal intercourse
with the following partner type:
- Relationship partner (n = 19)
Men
(N = 122)
Women
(N = 80)
0%
11.1%
- Casual/darting partner (n = 83)
8.5%
24.4%
- Friend (n = 33)
24.0%
44.4%
- New acquaintance (n= 36)
30.4%
30.8%
Shick et al., J Sex Med 2010 7(suppl): 315-329.
45
Why are older patients getting
infected?
3)Inadequate efforts of care providers to assess and
communicate risk
•
Infrequently assess risk (i.e., take a sex history)
- Fear of angering or insulting
- Shame or discomfort discussing sex with seniors
(imagine Grandma and Grandpa doing it!)
- Misinformed about sexual life of elders, perceive
their patients as being at low risk
•
Poor skills at taking a sex history
- Especially in persons > age 50 years
Loeb et al., J Gen Intern Med 2011 7(suppl): 315-329.
46
Older Women
Immune reconstitution
Co-morbid illnesses
Limited incomes
Delay in testing
Poly-pharmacy
Issues specific to
older women
Insufficient data on
drug interactions in older pop
Unprotected sex
Nauen E. AIDS: A woman’s disease. 2002; Clark RA, Bessinger R. J Acquir Immune
Defic Syndr Hum Retrovirol. 1997; Adler WH, et al. Mech Ageing Dev. 1987.
47
Gender Differences in HIV Natural
History
Risk Factors for HIV Transmission
Women are more susceptible than men to
contract HIV through heterosexual intercourse
Factors that increase
the risk of transmission
Presence
of STD
Stage of disease
in partner
Role of
contraception
Exposure site
(oral, vaginal, anal)
Substance use
Social/behavioral
Age
DHHS. HRSA Care Action. HIV disease in women of color. 1999; NIAID. NIH. Fact Sheet. HIV
infection in women. 2002; Fowler MG, et al. Obstet Gynecol Clin North Am. 1997; Lazzarin A,
et al. Arch Intern Med. 1991.
49
Viral Loads in Women
Viral load lower in women
Moore (VI)*1173
Sterling (1999)71
Evans 42
Sterling (2001)202
Moore (V)*
Farzadegan527
Anastos (IV)*2859
Rezza 415
Lyle 149
Moroni 2011
Anastos (III)*
Moore (IV)*
Katenstein 391
Junghans (H)*1337
Junghans (IDU)*
Anastos (II)*
Moore (III)*
Bush 40
Anastos (I)*
Moore (II)*
Moore (I)*
Kalish 494
*Number represents total in study and not total in strata.
Gandhi M, et al. 9th CROI, 2002. Abstract 775-W.
Viral load higher in women
750
675
600
525
450
375
CD4 count
Study N
300
225
150
75
0
50
Progression to new AIDS diagnoses or
death same in both sexes
Period of
follow-up
~2 yrs
Cohort
Johns Hopkins clinic cohort1,2
3 yrs
Swiss HIV Cohort Study2
4 yrs
London clinic cohort, 1st HAART on3
5.4 yrs
6 yrs
1Sterling.
Italian Antiretroviral Treatment Group, 1st HAART
onwards4
EuroSIDA cohort, 1st HAART on5
AIDS 2001; 2Junghans. AIDS 1999; 3Moore A. JAIDS 2002; 4Nicastri. AIDS
2005; 5Moore A. JAIDS 2003 [ Slide adapted from Monica Ghandi MD, UCSF)
51
Rates of other clinical events same in
both sexes in HAART era
Event
Cohort and response
Mortality
French prospective cohort (APROCO)1 Pts. starting PI’s; AIDS
mortality same (non-AIDS mortality women/men 1.6)1 (2-3 yrs)
Mortality
CASCADE2 (22 cohorts, Europe, Australia, Canada); Survival
same2 (HAART era)
Admissions
JH clinic3 OI admissions same (non-OI admissions women/men
1.5)3 (1994-1998)
Admissions
Bronx opiate user cohort4 Hospitalizations same (women > men
pre-HAART) (HAART era)
1Lewden.
JAIDS 2001; 2CASCADE. Lancet 2003; 3Gebo. JAIDS 2003; 4Floris-Moore. JAIDS 2003
52
Slide adapted from Monica Ghandi, MD UCSF
Pharmacokinetics
How Women Differ
Drug
interactions
Lower body
weight
Hepatic
metabolism
Higher body
fat content
Effects of
pregnancy
Hormonal
differences
Hader SL, et al. JAMA. 2001; DHHS. Guidelines…, February 2002; Garcia PM, et al. Clinical
Update. 2000; Anderson GD. J Gend Specif Med. 2002; Mirochnick M. Ann NY Acad Sci. 2000; Mildvan D,
53
et al. J Acquir Immune Defic Syndr. 2002.
WOMEN AND ART: EFFICACY
AND COMPLICATIONS
54
Women and ART
 Do women and men have equal antiretroviral therapy (ART )
access?
 Are there differences in efficacy?
 Are wishes regarding pregnancy considered when ART
regimens are selected?
 Do long-term complication considerations differ for men and
women?
55
Access to Antiretroviral Therapy
 Low and Middle income countries (n=109) antiretroviral
coverage:
 Women 53%
 Men 41%
 US (based on medical monitoring project)
 Women 86% (95% CI: 83-89)
 Men
90% (95% CI: 88-92)
UNAIDS Global Report 2011
CDC, MMWR Dec 2, 2011
56
Overview
 Do women and men have equal antiretroviral therapy (ART )
access?
 Are there differences in efficacy?
 Are wishes regarding pregnancy considered when ART
regimens are selected?
 Do long-term complication considerations differ for men and
women?
57
Gender Distribution in Clinical Trials
Treatment-Naïve
Patient Trials
ACTG 320
GS 934
STRTMRK
ECHO/THRIVE
Women at Baseline (%)
17
13.5
19
24
58
Gender Distribution in Clinical Trials
Treatment-Naïve Patient Trials
Women at Baseline (%)
ACTG 320
17
GS 934
13.5
STRTMRK
19
ECHO/THRIVE
24
Treatment-Experienced
Patient Trials
Toro
Women at Baseline (%)
RESIST 1 and 2
DUET 125-206
DUET 125-216
BENCHMRK 1 AND 2
13.7
10
11.4
12
9
59
Antiretroviral Treatment in Women
Are there gender-based differences?
 FDA meta-analysis from 2000-2008
 39 randomized trials
 22,411 participants; 14 antiretroviral drugs
 Overall 20% women (25% naïve trials; 15% experienced)
 Enrollment of women declined from 2000 - 2008
 Concluded no clinically or statistically significant differences
in 48-week efficacy
 No gender differences for discontinuation due to adverse
events, loss to follow-up, or death
Soon G, et al 50th ICAAC. Boston, 2010
60
ACTG 5202: Sex and Race Differences in
Efficacy and Safety of Initial ART
 In females, but not males, higher HR for VF with ATV/RTV vs EFV
 ABC/3TC arms: 2.90 (95% CI: 1.32-6.36; P = .004)
 TDF/FTC arms: 2.20 (95% CI: 0.97-4.98; P = .03)
 No difference in baseline CD4+ count for females vs males
1.0
Week 192 Probability of Remaining Free
of Virologic Failure in Females
0.8
Percent
0.6
0.4
0.2
0
EFV +
EFV +
ATV/r +
TDF/FTC ABC/3TC TDF/FTC
Smith KY, et al. CROI 2011. Abstract 536.
ATV/r +
ABC/3TC
61
CASTLE Trial: Treatment Naive
Atazanavir/r vs Lopinavir/r each with Tenofovir
and Emtricitabine
 96-week results
 Key: ATV/r Women (n=138)
LPV/r Women (n=139)
ATV/r Men(n=302)
LPV/r Men(n=304)
Intent to Treat (NC=F)
1.0
1.0
0.8
0.6
0.4
0.2
On Treatment
6
7
7
7
0.8
6
3
7
1
0
Squires et al. Jour Antimicrobial Chemotherapy Sept 2010
0.6
8
6
9
1
8
9
8
7
0.4
0.2
0
62
GRACE: Outcomes of DRV/RTV + OBR in Rx
Experienced Men and Women
 Multicenter, single-arm,
open-label, phase IIIb study
 Virologic response (ITTTLOVR analysis) not
significantly different in
women vs men at
48 wks
 Virologic failure rates similar
 Discontinuations more
common among women vs
men (32.8% vs 23.2%; P <
.05)
Squires K, et al. IAC 2008. Abstract MOPEB042.
Women
(n = 287)
Men
(n = 142)
50.9
58.5
73.0
(n = 200)
73.5
(n = 113)
Virologic failure, %
28.6
28.2
Discontinuations %
32.8
23.2
Outcomes at Wk 48
ITT-TLOVR (< 50c/ml) %
TLOVR-non-VFs
censored %
Reasons for discontinuation, %
Lost to follow-up
8.4
6.3
Adverse events
7.7
4.2
Consent withdrawal
4.5
4.2
Noncompliance
4.5
4.2
Virologic failure
2.1
2.8
Other*
5.6
1.4
*Included site closure, pregnancy, ineligibility to continue study, pt relocation,
failure to attend clinic visits, sponsor’s decision, safety in an elderly pt, no
decrease in HIV-1 RNA, time limitations on clinic visits, and new regimen
initiation.
Currier J et al. Ann Int Med 153:349-357
63
Real World: Are Virologic Suppression Rates in
Women as Good as Men?
 CDC Medical Monitoring project in US
 Proportion on antiretroviral therapy with suppressed viral
load
 Women 71% (95% CI: 68-75)
 Men who have sex with men 81% (79-84)
 Men who have sex with women 75% (71-79)
CDC MMWR Dec 2, 2011
64
Adherence to Treatment
Are there Gender Based Differences?
•
British Columbia Cohort of 545 drug users (37% women)
Factors associated with adherence <95%
Factor
Odds Ratio
95% Confidence
Int
P Value
Daily Cocaine
0.57
0.47-0.71
<0.001
Daily Heroin
0.56
0.43-0.70
<0.001
Age < 24 years
0.27
0.13-0.57
<0.001
Female
0.70
0.53-0.93
<0.013
High Baseline
Viral load
0.81
0.68-0.97
<0.018
Education
0.7
0.52-0.93
<0.04
Tapp C et al. BMC Infectious Disease 2011; 11:86
65
Antiretroviral Tolerability in Women
 Limited generalization on specific adverse events as relate to
gender
 Nausea generally more common in women while diarrhea
occurs more commonly in men1,2,3
1. Currier J et al. Ann Int Med 153:349-357
2. Squires et al. Jour Antimicrobial Chemotherapy Sept 2010
3. Hodder S, et al 49th ICAAC. San Francisco, , 2009. [Abstract H-919].
66
Overview
 Do women and men have equal antiretroviral therapy (ART )
access?
 Are there differences in efficacy?
 Are wishes regarding pregnancy considered when ART
regimens are selected?
 Do long-term complication considerations differ for men and
women?
67
Communication Gap
Women Living Positive Survey:
 48% who had been pregnant/
would consider pregnancy had
never been asked by HCP if they
had/were considering having
children
 57% who had been/were
currently pregnant had not had
preconception discussions with
HIV provider regarding treatment
options
ASK all women with
HIV of childbearing
age about their plans
regarding pregnancy
on a routine basis to
help ensure
informed decisions
regarding
contraception and/or
conception
Squires KE, et al. AIDS Pat Care STDs. 2011;25(5)
68
Antiretroviral Pregnancy Registry Study
(www.APRegistry.com)
 Enrolls approximately 1,500
women exposed to ART each
year (80% US)
 13,711 pregnancies with followup data through January 2011
Birth Defect
Rate (%)*
Any PI
(n=65)
3.01
 Overall birth defect rate
comparable to CDC populationbased surveillance data: 2.7%
versus 2.72%
Any NRTI
(n=124)
2.95
Any
NNRTI
(n=30)
2.7
 No specific birth defect patterns
detected
Any
NtRTI
* First
(n=14)
2.2
trimester exposur
Antiretroviral Pregnancy Registr5y. Interim Report, January 2011.http://apregistry.com/forms/exec-summary.pdf..f
69
Incidence of Birth Defects with 1st trimester
ART (www.APRegistry.com)
Referent rate 2.7% in general population
Defects/Live Births
(>200 reported 1st trimester exposures)
Prevalence %
(95% CI)
22/744
17/641
118/3864
19/797
26/1092
118/3620
3.0 (1.9, 4.5)
)
2.7 (1.5, 4.2)
3.1 (2.5, 3.7)
2.4 (1.4, 3.7)
2.4 (1.6, 3.5)
3.3 (2.7, 3.9)
PIs
Atazanavir
Indinavir
Lopinavir
12/502
6/285
16/738
2.4 (1.2, 4.1)
2.1 (0.8, 4.5)
2.2 (1.2, 3.5)
Ritonavir
33/1401
2.4 (1.6, 3.3)
NNRTIs
Efavirenz
Nevirapine
17/623
25/987
2.7 (1.6, 4.3)
2.5 (1.6, 3.7)
NRTIs
Abacavir
Emtricitabine
Lamivudine
Stavudine
Tenofovir DF
Zidovudine
Antiretroviral Pregnancy Registr5y. Interim Report, January 2011.http://apregistry.com/forms/exec-summary.pdf..f
70
Overview
 Do women and men have equal antiretroviral therapy (ART )
access?
 Are there differences in efficacy?
 Are wishes regarding pregnancy considered when ART
regimens are selected?
 Do long-term complication considerations differ for men and
women?
71
Key Comorbidities in Women with HIV
Risk of death after HIV
diagnosis, 1996-2001
(CASCADE)
Osteoporosis
Cardiovascular
Disease
88% reduction
in
excess mortality
72
Fracture Prevalence Greater in HIV
Patients
3.0
Women
P=0.002
HIV
Non-HIV
2.5
2.0
1.5
P=0.01
1.0
P=0.01
P=0.53
0.5
0
Fracture Prevalence/100 Persons
Fracture Prevalence/100 Persons
• Population: 8,525 HIV+ and 2,208792 HIV• Patients with fracture: 245 HIV+ and 39,073 HIV• Overall fracture prevalence (per 100 persons): 2.87 HIV+ and 1.77 HIV3.0
Men
P<0.0001
HIV
Non-HIV
2.5
2.0
1.5
1.0
P=0.001
P<0.0001
P=0.001
0.5
0
Any
Vertebral
Hip
Wrist
Triant VA et al. J Clin Endocrinaol Metab. 2008;93(9):3502.
Any Vertebral
Hip
Wrist
73
Association of Osteoporosis with Antiretroviral
Therapy
Antiretroviral Therapy Overall Protease Inhibitor Therapy
Study
Odds ratio (95%CI)
Study
Odds ratio (95%CI)
Amiel (2004)
2.41 (0.77, 7.58)
Amiel (2004)
0.61 (0.21, 1.72)
Bruera (2003)
4.81 (0.60, 38.74)
Brown (2004)
11.09 (0.57, 217.66)
Garcia (2001)
1.60 (0.13, 19.84)
Bruera (2003)
1.18 (0.37, 3.78)
Knobel (2001)
2.68 (0.70, 10.33)
Dolan (2004)
0.71 (0.11, 4.51)
Knishi (2005)
0.84 (0.03, 22.43)
Huang (2002)
1.57 (0.05, 43.79)
Mededdu (2004)
11.00 (0.65, 187.76)
Knobel (2001)
1.97 (0.47, 8.27)
Vescini (2003)
0.54 (0.05, 5.68)
Mededdu (2004)
2.63 (1.13, 7.03)
Mondy (2003)
1.89 (0.23, 15.81)
Nolan (2001)
3.25 (2.08, 9.83)
Tebas (2000)
1.83 (0.35, 9.62)
Vescini (2003)
1.24 (0.34, 4.52)
Yiu (2005)
0.77 (0.15, 2.34)
Overall (95%CI)
1.57 (1.05, 2.34)
Overall (95%CI)
0.01
2.38 (1.20, 4.75)
Odds ratio
100
Caveat: Few studies adjusted for age or
duration of infection
Brown TT et al. AIDS. 2006, 22:2168.
0.01
Odds ratio
100
74
Cumulative Use of TDF and/or Boosted PIs and
Risk of Osteoporotic Fractures
 Retrospective analysis of 56,660 HIV+
male veterans enrolled from 1988-2009
 Osteoporotic fractures assessed from
ICD-9 codes
 Cumulative use of TDF and/or boosted PI
associated with higher risk in ART era,
after controlling for risk factors
HR for Fracture,
HAART Era
1.3
 Cumulative use of ABC, thymidine
analogues, NNRTIs not associated
with higher risk
Bedimo R, et al. IAS 2011. Abstract MOAB0101.
1.0
TDF
Boosted PI
Univariate analysis
Controlled for effects of CKD, age, race, smoking,
DM, BMI, and HCV
Controlled for covariates in Model 1 plus
concomitant exposure to ARVs
 Cumulative use of LPV/RTV also
associated with higher fracture risk
PI association limited to LPV/RTV
1.1
0.9
 Highest risk with concomitant use
–
1.2
Limitations
–
Retrospective cohort study
–
BMD data not available
–
Fractures not verified to be
osteoporotic
75
• BMD declined in the first 48
weeks with subsequent
stabilization out to Wk 96‡
• No statistical difference
between treatment groups
at Wk 96 in either gender
• Trend towards greater BMD
changes in women for both
arms, but small sample size
(n<30)
Mean change from baseline
in BMD, %(95%CI)†
BMD* Changes by Gender
Mean Change from Baseline to Week
96
-1.7%
-1.7%
-2.5%
-2.7%
Baseline
RPV+FTC/TDF: Men
149
EFV+FTC/TDF: Men
152
RPV+FTCTDF: Women 34
EFV+FTC/TDF: Women 37
48
96
Time (Weeks)
132
130
28
29
119
131
27
28
*Measured by whole body dual energy x-ray absorptiometry (DEXA)
†95%CI = 95% confidence interval
‡Within group changes at Weeks 48 and 96 from baseline, p<0.0001 Wilcoxon signed-rank test
76
Short W, et al. 2nd International Workshop on HIV and Women: from Adolescence through Menopause 2012. Bethesda, MD. Oral # O14A
76
Per 100,000 Population
Age-adjusted Death Rates
Selected Diagnoses in Women (General Population)
200
140.9
150
110.0
100
60.7
44.0
50
41.5 40.0
23.4
32.8
0
Coronary Heart
Disease
Stroke
White Females
Source: NCHS and NHLBI.
Lung Cancer
Breast Cancer
Black Females
77
Cardiovascular Disease and HIV
DAD Study: 2003
• N=17,852 (24% women)
• High prevalence of multiple CVD risk factors
SMART: 2006
• N=5,472 (27% women)
• Better CV outcomes with continuous vs episodic ART
FRAM /MESA: 2009
• N=433 HIV-positive (30% women)
• HIV independently associated with increased risk of CVD,
particularly in women
78
Association of HIV and Atherosclerosis
Stronger in Women then Men
• Myocardial infarction hospitalization rates increased 1.75-fold in those
with HIV infection, with stronger association in women (RR=2.98) than
men (RR=1.40)1
• Fram study association of HIV infection with internal carotid intimamedial (iCIMT) thickening stronger in women compared with men2
Women
Estimated
iCIMT(m
m)
HIV
Current
smoker
0.200
0.182
Men
Estimated
iCIMT(mm)
95% CI
0.0820.318
0.0270.129
95% CI
HIV
0.128
0.1020.299
Current
smoker
0.155
0.0210.109
1. Triant VA, et al. J Clin Endocrinol Metab 2007; 92:2506–2512
2. Grunfeld C et al. AIDS 2009 23:1841-1849
79
CASTLE Study: Lipid Profiles by Gender
• Mean percentage change in fasting lipid concentrations in female
and male patients from baseline through week 96 (as-treated).
Squires K E et al. J. Antimicrob. Chemother.
2010;jac.dkq457
© The Author 2010. Published by Oxford University Press on behalf of the British Society for
Antimicrobial Chemotherapy.
80
Conclusions
 Overall women generally have equal access to me,
however, it is NOT optimal
 Despite comprising over slightly half of adults living with
HIV, women still constitute a minority of clinical trial
participants
 ART efficacy roughly similar in men and women in
registrational trials, though “real life” scenarios suggest
lower virologic suppression rates
81
Conclusions
 Planning for pregnancy should be a part of ART regimen
consideration, and often is not
 Osteoporosis and cardiovascular disease are important
complications in women with HIV
 30 years on, we have many triumphs, however, much more
research is needed
 Trial populations need more women!!
82
Women and HIV: Lactic Acidosis
 FDA received 60 reports of lactic acidosis associated with dual
nucleosides; 55% mortality1
 83% in women; 50% > 175 lbs
 Mean time on ART= 255 days
 85% of 20 fatal cases were in women
 Lactate levels measured in naïve pts treated with d4T containing
HAART
 15/ 31 African women responding to tx had AE
 20% severe hyperlactatemia vs 0% among 31 men
1. Boxwell DE et al 39th ICAAC, Abst 1284 1999
2. Gerard, Poster 69 7th IWADRL, Dublin 2005
83
Sex Differences in Toxicitythe NVP story
 NVP FDA approved in 1996 adults based on benefit in treatment
experienced patients
 2002 concern regarding toxicity in HIV negative HCW
 Early studies of NVP conducted in early 1990s included few women
 Reports of excess toxicity in women began to appear in literature
2001-2003
 2004 Dear Doctor Letter and Black Box warning added to label- sex
specific recommendation about use of nevirapine
84
Women and NNRTI toxicity
 9.5% women developed rash vs 1.1% men in a prospective trial
(Bersoff-Matcha Sj et al, CID 2001)
 Women 5 times more likely than men to develop rash to NVP or
EFV in retrospective review (Mazhude C et al, AIDS 2002)
 3 fold higher risk (5.8 vs 2.2%) of “symptomatic hepatitis” among
women on NVP
 Women with CD4+ cell counts >250 cells/mm3 11% risk
vs. 0.9% for women with CD4 + cell counts
<250cells/mm3
 Men with CD4+ cell counts >400 cells/mm3 6.3% risk vs
2.3% for men with CD4+ <400 cells/mm3
85
Pregnancy Considerations
 DHHS guidelines treatment goals: maximize maternal
health and prevent perinatal transmission1
 Use of combination therapy recommended during
pregnancy after first trimester unless woman already on
treatment
 Guidelines recommend elective C-section for women
with viral load >1000 copies/mL at term
 Benefit of elective C-section for women with
suppressed viral load has not been defined
86
Class
Nucleoside(tide) RTI
Non Nucleoside RTI
Protease Inhibitor
Fusion Inhibitor
Drug
Pregnancy Category
Retrovir (zidovudine, AZT)
Videx (didanosine, DDI)
Hivid (zalcitabine, DDC)
Zerit (stavudine, D4T)
Epivir (lamivudine, 3TC)
Ziagen (abacavir, ABC)
Viread (tenofovir, TDF)
Emtriva (emtricitabine, FTC)
C
B
C
C
C
C
B
B
Viramune (nevirapine, NVP)
Rescriptor (delavirdine, DLV)
C
C
Sustiva (efavirenz, EFV)
D
Fortovase (saquinavir, SQVHGC)
Invirase (saquinavir, SQVSGC)
Crixivan (indinavir, IDV)
Norvir (ritonavir, RTV)
Viracept (nelfinavir, NFV)
Agenerase (amprenavir, APV)
Kaletra (lopinavir/ritonavir, LPV/r)
Reyataz (atazanavir, ATV)
Lexiva (fos-amprenavir, f-APV)
B
B
C
B
B
C
C
B
C
Fuzeon (enfuvirtide, T-20)
B
Watts et al. Am J Ob Gyn 2004;191:985-92
Challenges for Treatment of Women
 Interventions used in pregnancy to prevent transmission can
select for drug resistance unless fully suppressive
combination therapy used.
 In resource limited settings, prior use of single dose
nevirapine to prevent transmission may have unintended
maternal consequences, hence standard of care is changing
 For women with higher CD4 cell counts, risk benefit ratio for
starting triple drug antiretroviral therapy during pregnancy
and continuing for life not fully defined but momentum for
lifelong ART (Option B+)
88
Background
• Nevirapine (NVP) is a cornerstone of antiretroviral treatment
(ART) globally
• Intrapartum single dose NVP (sdNVP) is widely used to
reduce MTCT, but leads to NVP resistance in the majority of
women
– Women with prior sdNVP exposure experienced higher rate
of virologic failure/death in OCTANE Trial 1 when treated
with NVP- compared with PI-based regimens
• Minimal data exist regarding the relative efficacy of NVPbased vs. PI-based regimens among antiretroviral-naïve
patients with no prior sdNVP exposure
A5208 OCTANE: Study Design
OCTANE Trial 1:
OCTANE Trial 2:
240 women with
prior SD-NVP
(superiority)
500 women with
NO prior SD-NVP
(equivalence)
LPV/r +
TDF/FT
C n=120
NVP +
TDF/FT
C n=120
LPV/r +
TDF/FTC
n=250
Two concurrent, open label, randomized clinical trials
NVP +
TDF/FT
C n=250
10 Study Sites, 7 Countries in Africa
BOTSWANA
KENYA
MALAWI
SOUTH AFRICA
UGANDA
ZAMBIA
ZIMBABWE
OCTANE Trial 1:
Results Among Women With Prior sdNVP
Exposure
KM Plot of Time to Virologic Failure or Death
Proportion alive and
without VF
1.0
p=0.0007
0.8
0.6
0.4
0.2
0.0
0
Randomized Arms
LPV/RTV
NVP
24
48
72 96 120 144
Study Week
Median
baseline
CD4 139
cells/mm3
Endpoints:
26% NVP
arm 8%
LPV/r arm
Adjusted
HR=3.6
(95%CI 1.77.5)
Number of Virologic Failures
NVP Resistance Detected by Standard
Genotyping at Baseline Associated with a
Primary Endpoint
NVP arm n=120
P=0.001
35
30
LPV/r arm n=119
(26%
)
25
P=0.006
20
15
(8%)
(73%)
10
(19%)
P=0.038
(9%)
(6%)
5
0
Overall
NVP
Resistance
Shahin
Lockman
No NVP
Resistance
% with Virologic Failure
Most Endpoints Occurred in Women
without Baseline Resistance by Standard
Genotype
Positive vs Negative
Identified by Standard Genotyping
100
Negative
80
Positive
60
40
20
0
NVP
LPV/r
A5208 OCTANE: Study Design
OCTANE Trial 1:
OCTANE Trial 2:
240 women with
prior SD-NVP
(superiority)
500 women with
NO prior SD-NVP
(equivalence)
LPV/r +
TDF/FT
C n=120
NVP +
TDF/FT
C n=120
LPV/r +
TDF/FTC
n=250
Two concurrent, open label, randomized
NVP +
TDF/FT
C n=250
Trial 2: Selected Eligibility Criteria
• HIV-1-infected women
• CD4 < 200 cells/mm3 in past 90 days
• Antiretroviral-naïve
(allowed up to 10 weeks of prior
zidovudine, more than 6 months previously)
• Estimated creatinine clearance > 60mL/min
Trial 2:Primary Endpoint and Analyses
• Primary endpoint: time to death or virologic failure
– Virologic failure =
• confirmed plasma HIV-1 RNA level < 1 log10 below
baseline 12 weeks after treatment is initiated,
OR
• > 400 copies/mL at or after 24 weeks
• Study powered to assess equivalence
– Defined as 95%CI for the hazard ratio [HR]: 0.5-2.0
• Primary analyses intent to treat
KM Plot of Time to Primary Endpoint
(Virologic Failure or Death)
• 92 women reached
an endpoint:
1.0
0.8
-50 (20%) in LPV/r
arm
-42 (17%) in NVP arm
• Hazard ratio: 0.85
(95% CI 0.56, 1.29)
0.6
0.4
Randomized Arms
LPV/RTV
0.2
NVP
0.0
• As-treated analysis:
Hazard Ratio: 0.71,
(95% CI 0.45, 1.13)
0
24
48
72
96
Study Week
120
144
168
Proportions Experiencing Virologic Failure vs. Death
KM Plot of Time to Permanent Discontinuation of
NVP or LPV/r
• 93 women
discontinued NVP or
LPV/r in 1st
regimen:
1.0
- 70 (28%) in NVP arm
- 23 (9%) in LPV/r
arm
0.6
(HR 3.4, 95% CI 2.2,
5.5)
• 35 (14%) in NVP
arm vs. no women
(0%) in LPV/r arm
discontinued due to
adverse event
0.8
0.4
Randomized Arms
LPV/RTV
NVP
0.2
0.0
0
48
96
Study Week
144
192
Adverse Events Among Women Taking
NVP vs. LPV/r
Event
NVP arm
n=249
LPV/r arm
n=251
Grade 3 or 4 sign/symptom*
Skin
34 (14%)
9
41 (16%)
2
Grade 3 or 4 lab test value*
Absolute neutrophil count
LFT/hepatic
Renal
64 (26%)
31
18
2
54 (22%)
21
9
8
Stopped ART due to any AE
Hepatic event
Rash
Hepatic event+rash
35 (14%)
20
12
3
0
*Only includes sub-categories with differences in count (between regimens) of >5
Conclusions
• Treatment with NVP+TDF/FTC has equivalent
virologic efficacy compared to treatment with
LPV/r +TDF/FTC among treatment-naïve women
with CD4 < 200 cells/mm3
– Previously-reported inferiority of NVP (vs. LPV/r) in
OCTANE Trial 1 was likely related to NVP resistance
from prior sdNVP exposure
• Treatment discontinuation due to adverse events
was more frequent with NVP
Summary
HIV among women is an ongoing problem in
the US
 Especially among low income women of
color
 Diagnosis often made during pregnancy
Greater awareness and more widespread
testing not linked to “risk groups” needed for
women
Optimal treatment strategies for women
throughout the lifespan need to be identified
103