Title: 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
1The potential role of human papillomavirus
(HPV) infection in vertical HIV
transmissionHPV co-infection in subtype C
HIV-1-infected pregnant women in Zimbabwe
- David Hill, PhD
- Stanford University
- 25 September 2006
2(No Transcript)
3HPV what is it?
- a DNA virus that causes epithelial proliferations
at cutaneous and mucosal surfaces - 106 genotypes have been identified (likely 100
more) gt30 infect anogenital epithelium - HPV is transmitted by skin-to-skin contact
- Biggest single risk factor high of sexual
partners
4HPV what is it?
- Genital infection with HPV is the worlds 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 gt90 clear within 2
years - Median duration of new infection 8 months
- Persistent infection with high-risk types causes
almost all (99) cervical cancer
5HPV whats 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
6HPV 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
7HPV vaccines
- June 2006 the US FDA licensed Mercks 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.
8HPV 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 individuals
lifetime risk of developing cervical cancer by
50 - (no ref)
9HPV purpose of our study
- 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
10Rationale 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
11This,in the context of HIV ?
12Global 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
13(No Transcript)
14Children (lt15 years) estimated to be living with
HIV end 2005 N
Total children living with HIV 2.3 million
UNAIDS, World Health Organization
15Children (lt15 years) estimated to be living with
HIV, and dying of AIDS end 2005 N
Total children living with HIV 2.3 million Total
children dying of AIDS 570,000
UNAIDS, World Health Organization
16Features 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 lt 0.10 0.50
Condition Chronic Fatal
LM Newell et al, Lancet 2004 364 and L Mofenson
17Research in PMTCT of HIV1994
Name of protocol Sites Therapy MTCT rate() v. placebo
PACTG 076 USA, France ZDV v. placebo 8 v. 25
EM Connor et al, NEJM 1994331
18Incident pediatric AIDS Cases in the
U.S.acquired via perinatal HIV, 1985-1999
Number of Cases
Quarter-Year
CDC
19Five antiretroviral therapy (ART) trials for
PMTCT1999-2003
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 ZDV3TC 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 ZDV3TC short v. Single dose NVP 9 v. 12
Dabis 1999 Wiktor 1999 Saba 2002 Jackson 2003
Moodley 2003 pooled analysis in Leroy AIDS 2005
20So, what did we find? ?
21Prevalence of HPV and types of HPV
HPV status Total N57
HPV Positive HPV Negative 44 (77) 13 (23)
HPV Positive HPV Negative
HPV type n
6 2
11 1
16 3
18 4
26 1
31 1
33 1
40 1
45 1
52 4
53 6
54 1
55 4
HPV type n
56 3
58 9
59 9
61 8
66 8
68 2
69 7
70 5
73 3
AE2 4
Pap155 3
Pap291 1
Generic only 10
22Maternal characteristics, by HPV status (N57)
No statistically significant differences were
identified across groups in any category
Characteristic Maternal HPV status Maternal HPV status
Characteristic Positive Negative
n44 n13
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
23 Prevalence of maternal HPV, by infant HIV
status
HPV status Total N57 Infant HIV infection status Positive Negative Unknown n6 n37 n14 Infant HIV infection status Positive Negative Unknown n6 n37 n14 Infant HIV infection status Positive Negative Unknown n6 n37 n14
HPV Positive HPV Negative 44 (77) 13 (23) 5 (83) 1 (17) 27 (73) 10 (27) 12 (86) 2 (14)
HPV Positive HPV Negative
24Prevalence of HPV by high and low risk groups in
all mothers and in groups of infant HIV status
HPV type Total
N57
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
25Prevalence of HPV by high and low risk groups in
all mothers and in groups of infant HIV status
HPV type Total Infant HIV infection status Positive Negative Unknown Infant HIV infection status Positive Negative Unknown Infant HIV infection status Positive Negative Unknown
N57 n6 n37 n14
Any high-risk type 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)
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
26Logistic regression models Risk of vertical HIV
transmission in HPV-positive and HPV-negative
mothers (adjusted for baseline maternal CD4 cell
count)
Maternal HPV type 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
a OR, odds ratio CI, confidence interval b
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
27Conclusions
- 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
28Acknowledgments
- David Katzenstein
- Bonnie Maldonado
- Julie Parsonnet
- Richard Roberts
- Kristin Cobb
- Avinash Shetty
- Catherine Ley
- Joel Palefsky
- Patrick Mateta
- Lynn Zijenah
29Factors affecting perinatal HIV worlds apart
- Developing, resource-poor
- Economic barriers
- Lack of infrastructure
- Lack of money
- Lack of people
- Social, cultural barriers
- Stigma
- Government barriers
- Lack of political will
- Industrialized, resource-rich
- Funding available
- Stable infrastructures
- Someone pays
- Robust health system
- Fewer social barriers
- Advocacy
- Governments act
- Advocacy