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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

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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

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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

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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

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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

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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)

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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

12UNAIDS, World Health Organization

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%)

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Sub-Saharan Africa2.1 mill. [91%]2.1 mill. [91%]

North America9 000 9 000 [0.4%][0.4%]

Total: 2.3 (2.1 – 2.8) million

Children (<15 years) estimated to be living with HIVChildren (<15 years) estimated to be living with HIVend 2005end 2005

N [%]N [%]

UNAIDS, World Health Organization

Total children living with HIV: 2.3 million

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Sub-Saharan Africa2.1 mill. [91%]2.1 mill. [91%]520,000 [91%]520,000 [91%]

North America9 000 [0.4%]9 000 [0.4%]100 [0.02%]100 [0.02%]

Total: 2.3 (2.1 – 2.8) million

Children (<15 years) estimated to be living with HIV, Children (<15 years) estimated to be living with HIV, and dying of AIDSand dying of AIDS

end 2005 end 2005 N [%]N [%]

UNAIDS, World Health Organization

Total children living with HIV: 2.3 millionTotal children dying of AIDS: 570,000

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Features of perinatal HIV/AIDS: a “tale of two epidemics”

LM Newell et al, Lancet 2004; 364 and L Mofenson

Industrialized, RICH countries

Developing, POOR countries

Perinatal HIV burden ~1% 99%

AIDS mortality by 2 years

< 0.10 ~ 0.50

Condition Chronic Fatal

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Research in PMTCT of HIV1994

EM Connor et al, NEJM 1994;331

Name of protocol Sites Therapy MTCT rate(%) v. placebo

PACTG 076 USA, France ZDV v. placebo 8 v. 25

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Incident pediatric AIDS Cases in the U.S.acquired via perinatal HIV, 1985-1999

01 98 51 98 5 1 98 6 1 98 7 1 98 8 1 98 9 1 99 0 1 99 1 1 99 2 1 99 3 1 99 4 1 99 5 1 99 6 1 99 7 1 99 8

50

100

150

200

250

300

Quarter-Year

Num

ber

of

Cas

es

CDC

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Five antiretroviral therapy (ART) trials for PMTCT

1999-2003

Dabis 1999; Wiktor 1999; Saba 2002; Jackson 2003; Moodley 2003; pooled analysis in Leroy AIDS 2005

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+3TCThree 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

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So, what did we find?

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Prevalence of HPV and types of HPV

HPV status TotalN=57

HPV Positive

HPV Negative

44 (77%)

13 (23%)

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

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Maternal characteristics, by HPV status (N=57)

CharacteristicMaternal HPV status

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

No statistically significant differences were identified across groups in any category

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Prevalence of maternal HPV, by infant HIV status

HPV statusTotalN=57

Infant HIV infection status

Positive Negative Unknown n=6 n=37 n=14

HPV Positive

HPV Negative

44 (77%)

13 (23%)

5 (83%)

1 (17%)

27 (73%)

10 (27%)

12 (86%)

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

HPV type*Total

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, 66b 18, 26, 45, 59, 68, 69, 70c 16, 31, 33, 52, 58d 6, 11, 40, 54, 55e 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

HPV type*Total Infant HIV infection status

Positive Negative Unknown

N=57 n=6 n=37 n=14

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, 66b 18, 26, 45, 59, 68, 69, 70c 16, 31, 33, 52, 58d 6, 11, 40, 54, 55e 61, 73, AE2, Pap 155, Pap 291, generic probe positive only

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Logistic regression models: Risk of vertical HIV transmission

in HPV-positive and HPV-negative mothers(adjusted for baseline maternal CD4+ cell count)

Maternal HPV typeTotal number of HIV+ mothers

HIV-infected infants

OR (95% CI)a Pb

Any HPVNone

3211

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1.90 (0.20 – 18.42)1.0

0.58

High riskc

Low riskd/Othere

None

231811

531

6.05 (0.61 – 59.78)1.50 (0.24 – 9.38)1.0

0.120.67

a OR, odds ratio; CI, confidence intervalb 2-tailed P valuec High-risk HPV: any 16-like, 18-like, or 56-like HPVd Low-risk HPV types: 2, 6, 11, 13 , 32, 40, 42, 44, 54, 55, 57, 62, 72e Other HPV types: 61, AE2, Pap155, Pap291, 73, mixture, or consensus probe positive only

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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

• 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

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