HPV VACCINE IN HIV-INFECTED WOMEN

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HPV VACCINE IN HIV-INFECTED WOMEN

• F GUIDOZZI
• Department of Obstetrics and Gynaecology
• Faculty of Health Sciences
• University of Witwatersrand.

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HPV VACCINE IN HIV-INFECTED WOMEN

• Speculative
• HPV Infection and Cervical Disease in HIV-
  infected women
• Immune Memory
• HBV vaccine in HIV infected women
• Personal view

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HPV VACCINE IN HIV- INFECTED WOMEN

• Prevalence of HPV infection much more in
  HIV-infected
• HIV ve
  29.8
• HIV ve, CD4 gt200, RNAlt20,000
  51.7
• HIV ve, CD4 gt200, RNA gt20,000
  66
• HIVve, CD4 lt200
  76
• 
  WIHS Women s Intravenous HIV Study

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HPV PREVALENCE IN HIV ve and HIV-ve Women
THE HIV EPIDEMIOLOGY RESEARCH STUDY ( HERS )

• 
  HPV ve HPV-ve
• ANY HPV 64
  27
• /gt 2HPV 37.8
  19.6
• Association with age No
  Inverse
• 
  68.5 to61.9
  48.7 to 7.7
• HIV ve women were 2.1 x more likely to have
  high-risk HPV and 2.7 x more likely to have
  low-risk HPV, both being more common in women
  with lower CD4 cell counts

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HPV PREALENCE IN HIV ve AND HIV-ve WOMEN

• Similar Results From Several Other Studies
• ALIVE STUDY 184 HIV ve
  84 HIV -ve
• 
  68 26
• NEW YORK STUDY 328 HIV ve
  325 HIV ve
• 
  54 32
• ALIVE STUDY AIDS Link To Intravenous Experience
  Study

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HPV Types Among HIV-Infected Women

• 20 Studies, 5578 HIV ve women,
  META-ANALYSIS
• No cytological abnormalities HPV
  prevalence was 36
• MOST COMMON HIGH-RISK TYPES
  WERE
• 16 (4.5)
• 58 ( 3.6)
• 18 (3.1 )
• 52 ( 2.8 )
• 33 ( 2.0 )
• HPV 16 most common in women with ASCUS/
  LSIL
• Women with HSIL were more likely to be
  infected with
• HPV 11, 18, 33, 51, 52, 53, 58,
  and 61 instead of HPV 16

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HPV PERSISTENCE AND CERVICAL DYSPLASIA

• Several studies, including the HERS and WIHS,
  have shown greater persistence of HPV infection
  in HIV ve women
• 
  HERS
• All HPV types more likely to persist in HIV ve
  than HIV ve ( OR 2.5 )
• Persistence was 1.9 x greater with CD4 cell
  counts lt 200 than gt 500
• 15-40 of HIV ve evidence of dysplasia 10-11
  x greater than HIV-ve
• Frequency and severity of abnormal Pap smears
  and histologically
• documented dysplasia increase with
  declining CD4 cell counts
• Dysplasia is associated with more extensive
  cervical involvement and often involves other
  sites ( vagina, vulva, perianal region )
• HERS HIV EPIDEMIOLOGY RESEARCH STUDY,
  WIHS WOMENS INTRAVENOUS HIV STUDY

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HIV INFECTION AND CERVICAL DYSPLASIA

• PREVALENCE OF
  CYTOLOGIC ABNORMALITIES
• 
  HIV ve
  HIV ve
• WIHS
  38
  16
• HERS
  19
  8
• BALTIMORE
  13
  2
• ZIMBABWE
  26
  7
• Risk factors include lower CD4 cell counts, HPV
  DNA positivity, previous abnormal cytology

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HIV and CERVICAL INVASIVE CANCER

• HIV ve women present at more advanced stages (
  especially with CD4 cell counts lt 200 ) and may
  metastasize to unusual locations ( psoas,
  clitoris, meninges)
• HIV ve women have poorer response to standard
  therapy, higher recurrences and death rates,
  shorter intervals to recurrence or death compared
  with HIV -ve of similar stage
• HIV ve women with invasive cervical cancer tend
  to be younger than HIV -ve

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PREVALENCE OF HPV IN CERVIX AND ANUSSUN STUDY

• 
  CERVIX ANUS
• ALL TYPES
  86 92
• HIGH RISK
  64 84
• LOW RISK
  59 74
• MEAN NO HPV TYPES 2.5
  4.4
• HIGH RISK
  1.4 2.7
• LOW RISK
  1.2 1.7
• SUN STUDY Study To Understand The Natural
  History Of HIV/AIDS in Era of Effective Therapy

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ANOGENITAL CYTOLOGICAL ABNORMALITIES

• Overall prevalence of abnormal Pap smears
• 34 for ANUS and
  29 for CERVIX
• 49 of women normal at both sites
• 12 of women abnormal at both sites
• 21 of women abnormal at anus only
• 18 of women abnormal at cervix only
• History of anal sex was not predictive of an
  abnormal anal pap
• 42 with a history of anal sex had an abnormal
  anal pap
• 30 with no history of anal sex had an abnormal
  anal pap

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HPV/HIV COINFECTION IN ERA OF HAART

• Impact of HAART on HPV infection and anogenital
  neoplasia remains unclear
• Several US, French and Italian studies have
  shown no reduction in prevalence of infection in
  women on HAART although only limited amount of
  follow-up
• Mixed reports on effect of HAART on CIN. Several
  studies have shown decrease in prevalence of CIN
  ( FRENCH ), regression of CIN and less likely
  progression of CIN ( WIHS ). However, other
  studies reported no difference with HAART
• Palefsky et al found no reduction in anal HPV
  infection. Men on HAART had higher rates of HG
  HPV with higher persistence rates

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HPV/HIV COINFECTION IN ERA OF HAART(cont)

• Assessed anal HPV infection and anal SIL 6
  months prior to and 6
  months after initiating HAART in 98 MSM and found
  no reduction
• Same authors found higher rates of persistent
  infection and of SIL in men on HAART
  than non treated men
• Prevalence of infection and SIL did not differ
  between patients whose CD4 cell count increased
  by at least 150
• LONDON 8640 HIV ve MSM .......rate of anal
  cancer increased from 35 per 100000
  pre-HAART to 92 per 100000 after introduction of
  HAART
• Incidence of anal cancer in HIV ve MSM is
  twice that of HIV ve men

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HPV VACCINE IN HIV INFECTED WOMEN

• Although HIV infected women have a higher
  prevalence of HPV infection with subtypes
  6, 11, 16 and 18, they are unlikely to be
  infected with all types at the same time
• 
  HER STUDY
• HPV TYPE
  PERCENT
• 6,11,16,18
  15.9
• 6 and 11
  3.1 and 0.9
• 16 and 18
  5.7 and 6.1

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SOUTH AFRICAN EXPERIENCE

• 400 HIV infected women in MACH-1 Trial
• 76 were positive for at least one high risk HPV
  type, 24 had no high risk HPV types. Lower
  CD4 cell counts and higher viral loads were
  only significant predictors.
• At baseline, 35 had LSIL, 13 had HSIL, 7 had
  ASCUS and 45 were normal
• Of those with normal pap or ASCUS 47 had high
  risk HPV, c w 90 in LSIL and 94 in HSIL
  respectively
• Women diagnosed with LSIL and HSIL were
  significantly more likely to be high risk HPV DNA
  positive , have low CD4 cell counts and higher
  viral loads
• MACH-1 Trial Management of Abnormal
  Cytology In HIV-1 Positive Women

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PREVALENCE OF HIGH RISK HPV

• No high risk HPV types
  24
• At least 1 high risk type
  76
• Number of different types
• 1
  
  27
• 2
  
  21
• 3
  
  12
• 4
  
  10
• 5
  
  4
• 6
  
  2
• 7
  
  1
• 8
  
  1

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PREVALENCE OF HIGH RISK HPV TYPES AT BASELINE

• HIGH RISK HPV TYPE
• 16
  16
• 52
  15
• 53
  15
• 35
  14
• 18
  
  11
• 45
  
  9
• 51
  
  9
• 68
  
  9

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PREVALENCE OF HIGH RISK TYPES

• During course of study, 6 month incidence of high
  risk HPV infection was 22
• Only significant predictor for incident infection
  was low CD4
• Clearance occurred in only 6 of cases. Lower HIV
  viral load was the only significant predictor for
  clearance. No association with CD4 counts and
  clearance
• 94 of infections persisted more than 18 months
• Regression of LSIL to normal during 18 months
  occurred in 11 and from HSIL to normal or LSIL
  in 27
• Progression of ASCUS to LSIL or HSIL seen in 17,
  whilst from LSIL to HSIL occurred in 4

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SUMMARY OF SOUTH AFRICAN PERSPECTIVE

• High prevalence (76) of HPV infection in HIV
  infected women, esp in the most immune
  compromised with lowest CD4 and highest viral
  loads
• High rate of abnormality on cytology 55
  abnormal pap, the majority having LSIL
  reflecting high rate of HPV infection and 13
  having HSIL
• From Clifford et HPV type distribution was HPV
  16, 58, 52, 31, 33
• From Denny et al, distribution was HPV 16, 58,
  52, 31, 18, 35
• Infection persisted in gt90 and clearance
  occurred in only 6 which was related to viral
  load and not CD4 count
• High risk HPV status was most powerful predictor
  of cytology progression. No cancer developed in
  the 3 year follow up
• Having CD4 gt 500 was protective against SIL
  suggesting that immune competent HIV infected
  women will behave like HIV ve women with regard
  to cervical disease
• No significant effect by antiretroviral drugs
  on development of high risk HPV infection or of
  cytological progression

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Principles of Vaccination

• The ultimate goal of vaccination is long-term
  disease protection1
• Vaccination stimulates the immune system to
  produce protective (neutralizing) antibodies to
  specific pathogens1
• THREE IMPORTANT CONCEPTS.
  
• Measuring antibody titers, without correlation
  with clinical efficacy, do not necessarily
  predict protection2
• Long-term clinical efficacy is the best measure
  of protection afforded by a vaccine against the
  target disease3
• Through the generation of immune memory,
  vaccination provides long-term protection against
  disease1

1. Epidemiology and Prevention of Vaccine-
Preventable Diseases The Pink Book, 10th ed.
Center for Disease Control and Prevention, Public
Health Foundation 2008. 2. Sadoff JC, Wittes J.
J Infect Dis. 20071961279-81. 3. Clemens J,
Brenner R, Mall R et al. JAMA. 1996
275390-397.
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CHARACTERISTICS OF IMMUNE MEMORY RESPONSE

• A proportion of activated B cells will become
  memory B cells characterised by consistent, long
  term, low level antibody production
• Reintroduction of antigen will result in rapid
  large scale antibody production from memory B
  cells with a decreased lag time from exposure to
  response
• Anamnestic immune response antibodies have higher
  affinity for antigen than those generated during
  primary immune response
• Decline in antibody levels is not unexpected.
  Immune responses typically wane with time after
  antigen stimulation because clearance of antigen
  removes stimulus for further antibody production

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INDUCTION OF IMMUNE MEMORY BY QUADRIVALENT VACCINE

• 552 women, 16-23years, in a double blind,
  placebo-controlled study
• 11 ratio to receive 3 dose regimen of
  QUADRIVALENT or placebo with 3 year follow-up
• 241 subjects (114 QUADRIVALENT 127 placebo)
  further 2 year follow-up
• All extension subjects received QUADRIVALENT or
  placebo at 60 months
• RESULTS
• Serum anti-HPV levels declined post
  vaccination, but reached a plateau at month 24
  then remained stable through month 60.
• Administration of challenge dose induced
  classic anamnestic response with anti-HPV levels
  1 week post challenge reaching levels observed 1
  month after primary doses. At 1 month post
  challenge, levels were higher than those seen1
  month after dose 3

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IMMUNE MEMORY

• Antibody levels do wane with time and a
  proportion of subjects who received vaccine in
  original study were seronegative to one or more
  vaccine HPV types at month 60. Uncommon with
  HPV16
• All titre levels decreased substantially to month
  60, but 10-20 fold increase between 1week -1
  month after 4th dose in all HPV types
• Among 10-35 subjects who were anti HPV 6,11,18
  seronegative at month 60, 95-99 became
  seropositive to relevant HPV type 1 month post
  challenge, with 50-76 having levels above those
  at 1 month post dose 3 of original course
• However despite this, there were no breakthrough
  cases of HPV 6,11,18 infection or related
  disease caused by waning immunity over the 4.5
  years post vaccination (13 new HPV18 in placebo )
  

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LESSONS FROM HBV VACCINE IN HIV INFECTED

• Recommended, although guidelines lack consensus
• Dose unclear as to whether SINGLE or DOUBLE.
  Significantly better response with double dose in
  patients with CD4 gt 350 and lt viral loads, but
  no difference if associated high viral loads. 4
  studies support above, 3 showed no impact
• European Consensus Group 2x dose, WHO No
  preference
• Seroconversion occurs in only about 45-55
• Some suggestion that anamnestic reaction is
  attenuated especially if assoc with HIV induced
  immune attrition
• 2 studies to support that high antibodies may
  last long-term
• Concern that HBV vaccine may accentuate HIV
  progression

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GENERAL CONSENSUS OF HPV VACCINE IN
HIV INFECTED WOMEN

• Not only is HPV infection prevalent but
  persistent infection is most notable
• High risk HPV predominates in those who are most
  immune compromised
• Ano-genital disease
• High incidence of cytological abnormalities
• HPV vaccine will cover most commonly seen
  infection HPV types ,with data to support that
  HPV 16 and 18 are within 5 most common types
• 
  HOWEVER
• From HBV vaccine data only about 50-55
  sero-conversion
• Dose of vaccine not clearly defined
• Some concern that immune memory may attenuate
  with increasing immune compromise
• HIV status and timing of HPV vaccine may
  influence efficacy
• Data pertaining to invasive cervical cancer still
  not available
• Role of anti-retroviral agents still not clearly
  defined

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THANK YOU FOR YOUR ATTENTION