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HPV VACCINE IN HIV-INFECTED WOMEN

HPV VACCINE IN HIV-INFECTED WOMEN. F GUIDOZZI Department of Obstetrics and Gynaecology Faculty of Health Sciences University of Witwatersrand . HPV VACCINE IN HIV-INFECTED WOMEN. Speculative HPV Infection and Cervical Disease in HIV- infected women Immune Memory

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HPV VACCINE IN HIV-INFECTED WOMEN

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  1. HPV VACCINE IN HIV-INFECTED WOMEN F GUIDOZZI Department of Obstetrics and Gynaecology Faculty of Health Sciences University of Witwatersrand.

  2. 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

  3. HPV VACCINE IN HIV- INFECTED WOMEN • Prevalence of HPV infection much more in HIV-infected • HIV –ve 29.8% • HIV +ve, CD4 >200, RNA<20,000 51.7% • HIV +ve, CD4 >200, RNA >20,000 66% • HIV+ve, CD4 <200 76% WIHS = Women s Intravenous HIV Study

  4. HPV PREVALENCE IN HIV +ve and HIV-ve WomenTHE HIV EPIDEMIOLOGY RESEARCH STUDY ( HERS ) HPV +ve HPV-ve • ANY HPV 64% 27% • =/> 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

  5. 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

  6. 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

  7. 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 < 200 than > 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

  8. 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

  9. HIV and CERVICAL INVASIVE CANCER • HIV +ve women present at more advanced stages ( especially with CD4 cell counts < 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

  10. 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

  11. 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

  12. HPV/HIV COINFECTION IN ERA OF HAART • Impact of HAART on HPV infection and anogenitalneoplasia 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

  13. 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

  14. 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%

  15. 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

  16. 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%

  17. 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%

  18. 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%

  19. 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 >90% 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 > 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 anti–retroviral drugs on development of high risk HPV infection or of cytological progression

  20. 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. 2007;196:1279-81. 3. Clemens J, Brenner R, Mall R et al. JAMA. 1996; 275:390-397.

  21. 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

  22. INDUCTION OF IMMUNE MEMORY BY QUADRIVALENT VACCINE • 552 women, 16-23years, in a double blind, placebo-controlled study • 1:1 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

  23. 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 )

  24. 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 > 350 and < 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

  25. 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

  26. THANK YOU FOR YOUR ATTENTION

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