The potential role of human papillomavirus
(HPV) infection in vertical HIV transmission:
HPV co-infection in subtype C HIV-1-infected pregnant women in
Zimbabwe
David Hill, PhD
Stanford University
25 September 2006
1
2
HPV: what is it?
• a DNA virus that causes epithelial proliferations at cutaneous and mucosal
surfaces
• 106 genotypes have been identified (likely ~100 more); >30 infect
anogenital epithelium
• HPV is transmitted by skin-to-skin contact
• Biggest single risk factor: high # of sexual partners
3
HPV: what is it?
• Genital infection with HPV is the world’s most common STI;
~80% of sexually active people are infected at some point in life
• Most HPV infection is transient, asymptomatic, resolves w/o treatment
– 70% clear within 1 year; >90% clear within 2 years
– Median duration of new infection: ~8 months
• Persistent infection with high-risk types causes almost all (99%+) cervical
cancer
4
HPV: what’s ‘high-risk’?
• High-risk types
– Associated with invasive
cancers (esp. cervical)
– common types:
16, 18, 31, 33,
35, 39, 45, 51, 52,
56, 58, 59, 68, 82
• Low-risk types
– Cause low-grade cell changes
and genital warts
– common types:
6, 11, 40, 42, 43
44, 54, 61, 72, 73, 81
5
HPV and cervical cancer
• HPV infection peaks in young women (early sexual activity)
• Cervical cancer typically follows 20-30 years later
• Cervical cancer affects 0.5 – 1.5 million women per year
– Kills nearly 0.25 million per year
• 80% of cervical cancer cases are in the developing world
– Major health inequity
• Highest incidence: sub-Saharan Africa & Latin America
• Prevention: regular gyn screening (pap) & treatment of precancerous
lesions
6
HPV vaccines
• June 2006: the US FDA licensed Merck’s Gardasil
– quadrivalent, protects against 6, 11, 16, 18
• Trials showed: safe, good immune response, efficacious
• Guards against 70% of cervical cancers and 90% of genital warts
• Later in June ’06: the Advisory Committee on Immunization Practices
(ACIP) recommended routine vaccination for girls 11-12 years; also made
vaccine available to 9-26 year olds.
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HPV vaccines
• GSK vaccine (still in phase III)
– bivalent, protects against types 16 & 18
• Why not develop a vaccine with 7 types?
Technical hurdles are many
• Mathematical models indicate that these vaccines (vs. 16 & 18) will reduce
an individual’s lifetime risk of developing cervical cancer by ~50%
(no ref)
8
HPV: purpose of our study
1.
To define prevalence and types of HPV in HIV-1-infected pregnant
women in urban Zimbabwe
– HPV prevalence reported elsewhere:
• ~30% in (sexually active) general population
– Estimated worldwide prevalence of 400-500 million
– Little geographic variation
• ~60% among HIV-infected women
2.
To pilot an investigation of the association of HPV infection with MTCT
– Based on our knowledge of other sexually transmitted infections
(STIs), and their role in facilitating HIV transmission
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Rationale for our study
• Much evidence of STIs amplifying HIV transmission
– Non-ulceratives: inflammation, increase local presence of targeted cells
– Ulcerative STIs: provide portals of entry
– Presence may increase amount of virus shed in genital tract
• STIs in the context of HIV has generally not included HPV
– HPV *should* be considered b/c of this potential influence on immune
response & physical lesions
• Our hypothesis is that HPV in genital tract will increase HIV shedding &
may facilitate HIV transmission to infants
• Understanding this relationship may help us develop more comprehensive
treatment & prevention strategies
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This,…in the context of HIV 
11
Global HIV and AIDS statistics by region,
end of 2005
N (%)
People living with
HIV
People newly infected
with HIV
Deaths due to AIDS
Sub-Saharan Africa
25.8 million (64%)
3.2 million (65%)
2.4 million (77%)
North America
1.2 million (3%)
43,000 (0.9%)
18,000 (0.6%)
World total
40.3 million (100%)
4.9 million (100%)
3.1 million (100%)
UNAIDS, World Health Organization
12
13
Children (<15 years) estimated to be living with HIV
end 2005
N [%]
North America
9 000
[0.4%]
Sub-Saharan Africa
2.1 mill. [91%]
Total: 2.3 (2.1 – 2.8) million
Total children living with HIV: 2.3 million
UNAIDS, World Health Organization
14
Children (<15 years) estimated to be living with HIV,
and dying of AIDS
end 2005 N [%]
North America
9 000 [0.4%]
100 [0.02%]
Sub-Saharan Africa
2.1 mill. [91%]
520,000 [91%]
Total: 2.3 (2.1 – 2.8) million
Total children living with HIV: 2.3 million
Total children dying of AIDS: 570,000
UNAIDS, World Health Organization
15
Features of perinatal HIV/AIDS:
a “tale of two epidemics”
Industrialized, RICH
countries
Developing, POOR
countries
Perinatal HIV burden
~1%
99%
AIDS mortality by 2
years
< 0.10
~ 0.50
Chronic
Fatal
Condition
16
LM Newell et al, Lancet 2004; 364 and L Mofenson
Research in PMTCT of HIV
1994
Name of protocol
Sites
Therapy
MTCT rate(%) v.
placebo
PACTG 076
USA, France
ZDV v. placebo
8 v. 25
EM Connor et al, NEJM 1994;331
17
Number of Cases
Incident pediatric AIDS Cases in the U.S.
acquired via perinatal HIV, 1985-1999
Quarter-Year
CDC
18
Five antiretroviral therapy (ART)
trials for PMTCT
1999-2003
Name of protocol
Sites
Therapy
Low MTCT rates (%)
v. placebo / other
ANRS049a/
DITRAME
Ivory Coast,
Burkina Faso
Short ZDV v.
placebo
15 v. 22
CDC-Retro-CI
Ivory Coast
Shorter ZDV v.
placebo
12 v. 22
PETRA
South Africa,
Tanzania,
Uganda
ZDV+3TC
Three arms plus
placebo
6 v. 9, 14, 15
HIVNET 012
Uganda
Single dose NVP v.
super short ZDV
12 v. 20
SAINT
South Africa
ZDV+3TC short v.
Single dose NVP
9 v. 12
Dabis 1999; Wiktor 1999; Saba 2002; Jackson 2003; Moodley 2003; pooled analysis in Leroy AIDS 2005
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So, what did we find? 
20
Prevalence of HPV and types of HPV
HPV status
HPV Positive
HPV Negative
Total
N=57
44 (77%)
13 (23%)
HPV type
n
HPV type
n
6
2
56
3
11
1
58
9
16
3
59
9
18
4
61
8
26
1
66
8
31
1
68
2
33
1
69
7
40
1
70
5
45
1
73
3
52
4
AE2
4
53
6
Pap155
3
54
1
Pap291
1
55
4
Generic only
10
21
Maternal characteristics, by HPV status (N=57)
No statistically significant differences were identified across groups in any category
Maternal HPV status
Characteristic
Positive
Negative
n=44
n=13
Age
Mean (SD)
Range
24.7 (5.0)
17-37
25.5 (6.1)
16-36
Years education
Mean (SD)
Range
9.2 (2.2)
2-13
9.7 (1.6)
7-11
Age at first intercourse
Mean (SD)
Range
18.9 (2.5)
12-26
18.0 (4.5)
6-24
No. sex partners, lifetime
Mean (SD)
Range
2.0 (1.2)
1-6
1.4 (0.7)
1-3
CD4+ cell count, cells/mm3
Mean (SD)
Range
344 (233)
11-1055
328 (143)
50-542
22
Prevalence of maternal HPV,
by infant HIV status
Infant HIV infection status
HPV status
Total
N=57
Positive
n=6
Negative
n=37
Unknown
n=14
HPV Positive
44 (77%)
5 (83%)
27 (73%)
12 (86%)
HPV Negative
13 (23%)
1 (17%)
10 (27%)
2 (14%)
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Prevalence of HPV by high and low risk groups
in all mothers and in groups of infant HIV status
Total
HPV type*
N=57
Any high-risk type
33 (58%)
High-risk, 56-likea
15 (26%)
High-risk, 18-likeb
23 (40%)
High-risk, 16-likec
15 (26%)
Low riskd
8 (14%)
Other/unk typese
22 (39%)
No HPV
13 (23%)
*Subgroups of subjects (by phylogenetic category) were not mutually exclusive.
a 53, 56, 66
b 18, 26, 45, 59, 68, 69, 70
c 16, 31, 33, 52, 58
d 6, 11, 40, 54, 55
e 61, 73, AE2, Pap 155, Pap 291, generic probe positive only
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Prevalence of HPV by high and low risk groups
in all mothers and in groups of infant HIV status
Total
HPV type*
Positive
Infant HIV infection status
Negative
Unknown
N=57
n=6
n=37
n=14
33 (58%)
5 (83%)
18 (49%)
10 (71%)
High-risk, 56-likea
15 (26%)
3 (50%)
5 (14%)
7 (50%)
High-risk, 18-likeb
23 (40%)
4 (67%)
11 (30%)
8 (57%)
High-risk, 16-likec
15 (26%)
1 (17%)
9 (24%)
5 (36%)
Low riskd
8 (14%)
1 (17%)
3 (8%)
4 (29%)
Other/unk typese
22 (39%)
2 (33%)
13 (35%)
7 (50%)
No HPV
13 (23%)
1 (17%)
10 (27%)
2 (14%)
Any high-risk type
*Subgroups of subjects (by phylogenetic category) were not mutually exclusive.
a 53, 56, 66
b 18, 26, 45, 59, 68, 69, 70
c 16, 31, 33, 52, 58
d 6, 11, 40, 54, 55
e 61, 73, AE2, Pap 155, Pap 291, generic probe positive only
25
Logistic regression models:
Risk of vertical HIV transmission
in HPV-positive and HPV-negative mothers
(adjusted for baseline maternal CD4+ cell count)
Total number of
HIV+ mothers
HIV-infected
infants
OR (95% CI)a
Pb
Any HPV
None
32
11
5
1
1.90 (0.20 – 18.42)
1.0
0.58
High riskc
Low riskd/Othere
None
23
18
11
5
3
1
6.05 (0.61 – 59.78)
1.50 (0.24 – 9.38)
1.0
0.12
0.67
Maternal HPV type
a
OR, odds ratio; CI, confidence interval
2-tailed P value
c High-risk HPV: any 16-like, 18-like, or 56-like HPV
d Low-risk HPV types: 2, 6, 11, 13 , 32, 40, 42, 44, 54, 55, 57, 62, 72
e Other HPV types: 61, AE2, Pap155, Pap291, 73, mixture, or consensus probe positive only
b
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Conclusions
• A high proportion of HIV-infected pregnant women in this population have
cervical HPV infection
• A broad diversity of HPV types is present
• There is a high prevalence of HPV types associated with increased risk of
cervical cancer
• This preliminary assessment of HPV carriage warrants further study of
– HPV types
– HIV cervical shedding
– the association between HPV and MTCT of subtype C HIV-1
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Acknowledgments
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David Katzenstein
Bonnie Maldonado
Julie Parsonnet
Richard Roberts
Kristin Cobb
Avinash Shetty
Catherine Ley
Joel Palefsky
Patrick Mateta
Lynn Zijenah
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Factors affecting perinatal HIV:
worlds apart
Industrialized, resource-rich
Developing, resource-poor
– Funding available
• Stable infrastructures
• Someone pays
• Robust health system
– Economic barriers
• Lack of infrastructure
• Lack of money
• Lack of people
– Fewer social barriers
• Advocacy
– Social, cultural barriers
• Stigma
– Governments act
• Advocacy
– Government barriers
• Lack of political will
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