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Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil
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Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil A.F. Nicol a,∗ , B. Grinsztejn b , R.K. Friedman b , V.G. Veloso b , C.B. Cunha b , I. Georg b , J.H. Pilotto c , R.I. Moreira b , C.A.V. Castro b , B. Silver d , R.P. Viscidi d a
Laboratory of Interdisciplinary Medicine, Instituto Oswaldo Cruz - FIOCRUZ, Rio de Janeiro, Brazil Instituto de Pesquisa Clínica Evandro Chagas, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil c Hospital Geral de Nova Iguac¸u & Laboratório de AIDS e Imunologia Molecular/IOC, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil d Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA b
a r t i c l e
i n f o
Article history: Received 5 December 2012 Received in revised form 4 February 2013 Accepted 8 February 2013 Keywords: HPV seroprevalence HIV/AIDS Pregnancy VLP Brazil Q vaccine
a b s t r a c t Background: Information on vaccine-type HPV seroprevalence is essential for vaccine strategies; however, limited data are available on past exposure to HPV-quadrivalent vaccine types in HIV-infected woman in Brazil. Objectives: To assess the seroprevalence for HPV types 6, 11, 16 and 18 in HIV-infected and uninfected women, from Rio de Janeiro, Brazil and to investigate potential associations with age and pregnancy status. Study-design: 1100-sera were tested by virus-like particle (VLPs)-based ELISA for antibodies to HPV types 16, 18, 6 and 11. Statistical analysis was carried out by STATA/SE 10.1 and comparisons among HIVinfected and HIV-uninfected women were assessed by Poisson regression models with robust variance. Results: HPV-6, 11, 16 and 18 seroprevalence was significantly higher among HIV-positive women (29.9%, 8.5%, 56.2% and 38.0%, respectively) compared to HIV-negative women (10.9%, 3.5%, 30.8% and 21.7%, respectively), when adjusted by age and pregnancy status. Overall, 69.4% of HIV-infected and 41.5% of HIV-uninfected women tested positive for any HPV quadrivalent vaccine type. However 4.7% and 1.1%, respectively, tested positive for all HPV vaccine type. In HIV-uninfected women who were pregnant, we found a higher HPV-11 seroprevalence (8.5% vs. 1.5%; P < 0.001) and a lower HPV 16 seroprevalence (22.6% vs. 34.2%; P = 0.010) compared to not pregnant women. HIV-uninfected women, aged 40 or more years old had a higher HPV 16 seroprevalence compared to women aged less than 40 years old. Conclusions: We did not observe a strong association between age and positive HPV antibodies nor an association between pregnancy and HPV seroprevalence. HPV seroprevalence was significantly higher among HIV-infected women compared to HIV negative women. In both populations the seroprevalence to all four HPV vaccine types was low suggesting that women may potentially benefit from the HPV vaccines. © 2013 Elsevier B.V. All rights reserved.
1. Background Cervical cancer continues to impose a significant health burden in low- and medium-resourced countries of Africa, Asia and Latin America.1 In Brazil, cervical cancer is the second most
∗ Corresponding author at: Laboratory Interdisciplinary of Medical Research – IOC/Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro, RJ, Brazil. Tel.: +55 21 3865 8133; fax: +55 21 2590 3495. E-mail addresses: nicol@ioc.fiocruz.br, [email protected] (A.F. Nicol), [email protected] (B. Grinsztejn), [email protected] (R.K. Friedman), [email protected] (V.G. Veloso), [email protected] (C.B. Cunha), ingebourg.georg@ipec.fiocruz.br (I. Georg), [email protected] (J.H. Pilotto), Ronaldo@fiocruz.br (R.I. Moreira), cavcastro@fiocruz.br (C.A.V. Castro), [email protected] (B. Silver), [email protected] (R.P. Viscidi).
common form of cancer among women and the fourth cause of death by cancer.2 Human papillomavirus (HPV) 16 and 18 account for approximately 70% of cervical cancer worldwide.3 Low risk HPV-6 and 11 types can cause more than 90% of cases of genital warts,4 which also impact on health services once it requires several consultations for its resolution. The majority of HPV infections are transient and clear within 2 years.5 HPV DNA testing mainly reflects current HPV infection status and is not a good measure of cumulative lifetime exposure to the virus. The serum antibody response to HPV virus-like particles (VLP), on the other hand, remains relatively stable over time, even after clearance of an HPV infection,6 and is therefore a candidate marker for cumulative HPV exposure, thus complementing HPV DNA detection. Several studies have consistently identified that HIV-infected women are at increased risk for HPV infection.7 Most of the studies
1386-6532/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcv.2013.02.007
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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on HPV seroprevalence in HIV-infected women have been carried out in women from high-resource countries,8 with scarce data available from resource limited settings. Knowledge of the burden of past infection with these HPV types among HIV infected women from Brazil will allow rationale utilization of HPV vaccines in this population.
pregnancy status. Statistical significance was defined by a Pvalue less than 0.05. Variables were described as percentages and prevalence ratios. Data were analyzed using STATA/SE 10.1 software.
2. Objectives
The mean age of the women was 36.7 years (SD 11.0 years); HIV-infected women were older (37.7) than HIV-uninfected (35.7) women. Table 1 presents the HPV-vaccine types seroprevalence according to HIV serostatus and the prevalence ratio for each type and the combined HPV-vaccine types between HIV-infected and uninfected women adjusted for age and pregnancy. Overall, 69.4% of HIV-infected and 41.5% of HIV-uninfected women tested positive for any HPV quadrivalent vaccine type. However, only 4.7% and 1.1%, respectively, of HIV-infected and HIV-uninfected women, tested positive for all four HPV vaccine types. HPV-16 was the type with the highest seroprevalence in both HIV-infected (56.2%) and HIV-uninfected (30.8%) women. The seroprevalence for each individual type and for all HPV-vaccine types was higher among HIV+ compared to HIV-negative women, when adjusted for age and pregnancy status. Concomitant seropositivity for HPV-16 and HPV-18 was observed in 32.3% of HIV-infected and 15.7% of HIV-uninfected women (data not shown). Table 2 compares the HPV seroprevalence among HIV-infected women by site. Seroprevalences for each HPV type and for concomitant HPV-vaccine type were statistically significantly higher among HIV-infected women from HGNI (a very poor metropolitan area in Rio de Janeiro) compared to HIV-infected women from IPEC. HPV seroprevalence by pregnancy status in HIV-infected and -uninfected women are depicted in Table 3. In HIV-uninfected women, HPV 11 seroprevalence was significantly higher among pregnant compared to non pregnant women (8.5% vs. 1.5%; P < 0.001). The opposite was found for HPV 16, e.g., a significantly lower seroprevalence among pregnant (22.6%) compared to non-pregnant (34.2%) HIV-uninfected women (P = 0.010). We did not find statistically significant differences in HPV seroprevalence according to pregnancy status in HIV-infected women. We did not observe statistically significant differences in adjusted models by age (data not shown). The HPV seroprevalence by age is depicted in Table 4. Among HIV-uninfected women, we found a statistically significant difference in age only for the HPV 16 seroprevalence outcome, e.g., women aged 40 or more years old presented a higher HPV 16 seroprevalence compared to women aged less than 40 years old (P = 0.020). Depicted in Table 5, are the few studies that evaluated HPV seroprevalence in Brazil. Higher HPV 16 seroprevalence was found among them, however different HPV seroprevalence was found according to the different stratifications and methods analyzed by the different studies.
The aim of the present study was to compare seroprevalence for HPV vaccine types 6, 11, 16 and 18 among HIV-infected and uninfected women, from Rio de Janeiro, Brazil and to investigate potential associations with age and pregnancy status. 3. Study design 3.1. Specimens A total of 1.100 serum stored samples collected between 2001 and 2008 from women under follow up at Institute of Clinical Research Evandro Chagas – IPEC/FIOCRUZ (N = 399), Hospital Geral de Nova Iguac¸u – HGNI (N = 134) and Dr Vasco Barcelos HIV Voluntary Counseling and Testing center (N = 568) were tested for HPV 6, 11, 16 and 18 antibodies; 532 (48.4%) samples were from HIVpositive (IPEC and HGNI) and 568 (51.6%) from HIV-negative (Dr Vasco Barcelos VCT) women. An age matched control criteria was used for selection of the HIV negative serum samples. Eighty-nine (16.7%) of the HIV-positive and 164 (28.9%) of the HIV-negative women were pregnant. 3.2. Assays Serum antibodies to HPV types 6, 11, 16, and 18 were measured by using VLP-based ELISA. HPV 6, 11, and 18 VLPs were produced in insect cells from recombinant baculoviruses expressing the L1 major capsid protein of individual HPV types, and HPV 16 VLPs were produced in mammalian cells from plasmids expressing the L1 and L2 capsid proteins. Specimens were tested in duplicate on separate plates, with retesting of specimens showing results exceeding a preset, acceptable coefficient of variation of 25%. Seropositivity was defined as an optical density (OD) value greater than the mean OD value plus 5 SDs, estimated by using serum samples from children of 1–10 years of age after exclusion of outliers. The cut-off point for HPV 6, 11, 16 and 18 was 0.200. 3.3. Statistical analysis Seroprevalence for each HPV-vaccine subtype (HPV-6, -11, 16 and -18) and for combined HPV-subtypes were calculated. Comparisons between HIV-infected and HIV-uninfected women (interest variable) were performed – controlling by age and pregnancy – using Poisson regression models with robust variance. Seroprevalence rates were compared according to sites, age and
4. Results
Table 1 HPV-vaccine type seroprevalence according HIV serostatus. Type
Total (N = 1100)
HIV(N = 568)
HIV+ (N = 532)
Unadjusted PR* (CI 95%)
Adjusted PR** (CI 95%)
HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type
221 (20.1) 65 (5.9) 474 (43.1) 325 (29.5) 31 (2.8) 605 (55.0)
62 (10.9) 20 (3.5) 175 (30.8) 123 (21.7) 6 (1.1) 236 (41.5)
159 (29.9) 45 (8.5) 299 (56.2) 202 (38.0) 25 (4.7) 369 (69.4)
2.7 (2.1–3.6) 2.4 (1.4–4.0) 1.8 (1.6–2.1) 1.8 (1.4–2.1) 4.4 (1.8–10.8) 1.7 (1.5–1.9)
2.7 (2.1–3.6) 2.7 (1.6–4.4) 1.8 (1.5–2.1) 1.8 (1.5–2.2) 4.8 (2.0–11.4) 1.7 (1.5–1.9)
* **
Unadjusted prevalence rate for “HIV serostatus: HIV-positive/HIV-negative” (reference: HIV-negative women). Adjusted prevalence rate for “HIV serostatus” controlled by age (reference: ≤30 years) and pregnancy status (reference: not pregnant).
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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Table 2 HPV seroprevalence by site of recruitment among HIV-positive women (N = 532). Type
Total (N = 532)
IPEC (N = 398)
HGNI (N = 134)
P-value
HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type
159 (29.9) 45 (8.5) 299 (56.2) 202 (38) 25 (4.7) 369 (69.4)
109 (27.4) 32 (8.0) 219 (55) 144 (36.2) 17 (4.3) 273 (68.6)
50 (37.3) 13 (9.7) 80 (59.7) 58 (43.3) 8 (6.0) 96 (71.6)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Table 3 HPV seroprevalence by pregnancy status in HIV negative and HIV positive women. Type
HPV 6 HPV 11 HPV 16* HPV 18 All HPV-vaccine type* Any HPV-vaccine type *
HIV-negative
HIV Positive
Not pregnant (N = 404)
Pregnant (N = 164)
P-value
Not pregnant (N = 443)
Pregnant (N = 89)
P-value
48 (11.9) 6 (1.5) 138 (34.2) 86 (21.3) 2 (0.5) 173 (42.8)
14 (8.5) 14 (8.5) 37 (22.6) 37 (22.6) 4 (2.4) 63 (38.4)
0.254 <0.001 0.010 0.738 0.064 0.343
129 (29.1) 36 (8.1) 248 (56.0) 163 (36.8) 19 (4.3) 308 (69.5)
30 (33.7) 9 (10.1) 51 (57.3) 39 (43.8) 6 (6.7) 61 (68.5)
0.379 0.537 0.817 0.197 0.319 0.855
Unadjusted model was presented, as we did not observe statistically difference when adjusted by age.
Table 4 HPV seroprevalence by age in HIV-negative and in HIV-positive women. Type
HIV negative women Total HPV 6 HPV 11* HPV 16** HPV 18 All HPV-vaccine type Any HPV-vaccine type HIV positive women Total HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type * **
Age
P-value
<30 years N (%)
30–39 years N (%)
40–49 years N (%)
≥ 50 years N (%)
160 16 (10) 13 (8.1) 39 (24.4) 40 (25) 4 (2.5) 66 (41.3)
205 19 (9.3) 3 (1.5) 57 (27.8) 37 (18.0) 1 (0.5) 77 (37.6)
145 19 (13.1) 2 (1.4) 58 (40.0) 37 (25.5) 1 (0.7) 67 (46.2)
58 8 (13.8) 2 (3.4) 21 (36.2) 9 (15.5) – 26 (44.8)
0.403 0.122 0.020 0.573 0.078 0.478
142 50 (35.2) 14 (9.9) 85 (59.9) 55 (38.7) 11 (7.7) 102 (71.8)
167 53 (31.7) 11 (6.6) 102 (61.1) 70 (41.9) 3 (1.8) 125 (74.9)
151 36 (23.8) 12 (7.9) 74 (49.0) 53 (35.1) 5 (3.3) 94 (62.3)
72 20 (27.8) 8 (11.1) 38 (52.8) 24 (33.3) 6 (8.3) 48 (66.7)
0.099 0.483 0.293 0.826 0.049 0.445
N (%)
Adjusted for pregnancy status, as we observed statistically difference for these variable and HPV 11. Unadjusted model was presented, as we did not observe statistically difference when adjusted by pregnancy status.
Table 5 HPV seroprevalence found on different Brazilians studies. Ref. Brazilian studies
Serology assay-type
Number of Brazilian serum assayed/total from the study
Stratification
HPV seroprevalence
Present study (2013)
VLP-based ELISA or HPV 6, 11, 16 and 18
1100/1100
Lu et al.28
VLP-based ELISA for HPV 16 Luminex Immuno Assay (HPV-4cLIA) for HPV 6, 11, 16 and 18 VLP-based ELISA for HPV 6, 11, 16 and 18
819/2.187
HIV infected and non infected women, pregnancy and age HIV neg. men baseline serostatus HIV infected women
HPV 6 (20.1%), HPV 11 (5.9%), HPV 16 (43.1%), HPV 18 (29.5%) HPV 16 (55%)
Firnhaber et al.16
Lu et al.29
Rama et al.22 Rama et al.15 Nonnenmacher et al.17
Sun et al.14
VLP-based ELISA for HPV 16 and 18 VLP-based ELISA for HPV 16 and 18 VLP-based ELISA-mixture antigen for HPV 6, 11, 16, 18 VLP-based ELISA for HPV 16
160/487
440/1477
HIV neg. men baseline serostatus
301/301
Primiparous young women
541/541
Adolescents and young health women Sexually active women
976/976
411/411
Invasive cervical cancer and controls
HPV 6 (46.9%), HPV 11 (21.9%), HPV 16 (29.4%), HPV 18 (18.1%) HPV 6 (19.5%), HPV 11 (25%), HPV 16 (16.1%), HPV 18 (10.5%) HPV 6 (5%), HPV 11 (2.7%), HPV 16 (9%), HPV 18 (7%) HPV 16 (14.60%), HPV 18 (6.46%) 32.7%
HPV 16 (47.4%),
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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5. Discussion Several studies have shown that immunization with HPV L1 VLPs is highly immunogenic and provides a high degree of protection against subsequent genital HPV infection, precancerous lesions, and cancers associated with vaccine-targeted genital HPV types.10–12 Limited data are available about HPV vaccine types 6, 11, 16 and 18 among HIV-infected, uninfected and pregnant women from Brazil. To our knowledge this is the first study that access and compare the seroprevalence of all 4 HPV types included in the quadrivalent vaccine according to HIV and pregnancy status and age in Brazil, thus providing data on past exposure to these HPV types that will be useful for vaccination strategy planning. A large Latin America study13 claimed that HPV seroprevalence in Latin American females is among the highest in the world (25%). In fact our study revealed an even higher overall HPV 6, 11, 16 and 18 seroprevalence; we detected a seroprevalence of 55% for any HPV type and 2.8% for all HPV vaccine types. Overall HPV 16 was the most prevalent type (43.1%), followed by HPV 18 (29.5%), HPV 6 (20.1%) and HPV 11 (5.9%). In a serological case–control study of invasive cervical cancer in Brazil the seroprevalence in controls was 24.4%.14 A serological study conducted in São Paulo, Brazil, in 2006 found a lower prevalence for HPV 16 (14.6%) and HPV 18 (6.4%) compared with our results.15 In our study, HPV seroprevalence for each and for all 4 HPVvaccine types was higher among HIV-infected compared with HIV-uninfected women. Our findings are in agreement with previous studies that reported higher HPV seroprevalence among HIV-infected women.7,9 In a study16 including 487 HIV-infected women from South Africa (N = 157) Botswana (N = 170) and Brazil (N = 160) using the Luminex Immuno Assay (HPV-4cLIA) for HPV 6, 11, 16 and 18, a higher overall seroprevalence, (approximately 65% to any one of the 4 HPV-vaccine types), was found compared to our results (55%). The seroprevalence to the individual HPV types differed from our findings, specially for the higher seroprevalence to HPV 6 and 11 in the former study. The differences may be attributed to subject selection, small sample size or more likely to differences in the assay methodology. We used a direct ELISA and the Firnhaber et al. study used a competitive inhibition assay with type specific monoclonal antibodies. Despite the fact that 69.4% and 41.5% of HIV-infected and noninfected women, respectively, were seropositive for at least one of the 4 HPV-types, only 4.7% and 1.1% of them were seropositive for all 4 HPV types. Thus only a small proportion of the women in our study had serological evidence of exposure to all 4 types included in the quadrivalent vaccine. Therefore those women who are at risk of HPV infection may benefit from vaccination, although the value of serostatus as a predictor of vaccine efficacy is still unknown at present. In the present study we found statistically significant difference in seroprevalence by site, which is most likely due to differences in past sexual behavior of the women sampled at the two sites. Lifetime number of sexual partners and earlier age of initiation of sexual intercourse are among the strongest determinants of HPV seroreactivity. Unfortunately no sexual history was obtained from study subjects; however, the HGNI site, which had the highest seroprevalence, recruited women from a poor metropolitan area of Rio de Janeiro and lower socioeconomic status is often associated with earlier age of onset of sexual activity and a greater lifetime number of sexual partners. In our study, pregnancy status and age did not modify the HPV seroprevalence, except for HPV 11 and for concomitant seropositivity for all 4 HPV-subtypes. The HPV 16 seroprevalence was higher in HIV negative women over 40 years of age compared to those less than 40 years of age. Among the HIV positive woman,
seroprevalence to all 4 HPV types was higher in women <30 years of age and >50 years of age compared to women 30–49 years of age; however, the number of subjects were small and the difference was of borderline significance. This suggests that young HIV-positive subjects are able to develop a long-lasting protective immunoresponse, reinforcing the concept that in women most genital tract HPV infections are transient, but most seroconversions are persistent.17 Although the incidence of HPV was increased over the course of pregnancy in some studies,18–20 the role of pregnancy in increasing the risk of HPV infection remains unclear. During the gestational period, a reduction in immunity and an imbalance in the vaginal flora may increase the risk of HPV infection. In the first trimester, the low immune response to HPV is associated with a higher persistence of HPV, which may clear during the third trimester with the recovery of immune response.21 Several studies have associated HPV seropositiity with age. We observed a trend of increasing seroprevalence with increasing age (>30 years old), with no statistically significant differences in seroprevalence by age, except for HPV 11 and 16 in HIV negative women. A recent serological study carried out in Brazil22 with young primiparous women found that 19.3% (N = 301) had antibodies to any of the 4 VLPs tested and seroprevalence to HPV 16 was higher than that to HPV 18, 11 and 6. The mean age of women in the study was 20 years. Another study from Brazil17 found an overall HPV seroprevalence of 39% for HPV 16, 18, 11 and 6. The lower seroprevalence found in these studies, compared with our study could be partially explained by the younger age of the subjects, since in both studies the methodological assays were done by VLPs. In general VLP assays are considered specific based on good correlations with type specific DNA detection and type specific seroconversions to incident DNA detection as documented in the few studies that included serial measurements. However, in human studies due to the high rate of exposure to multiple HPV types, low level cross reactivity cannot be entirely excluded. Although the increased combined antiretroviral therapy delivery in middle and low income countries has greatly decreased the burden of several opportunistic infections, and AIDS-related conditions, the impact of the partial immune restoration induced by antiretroviral therapy on the natural history of HPV infection seems modest, at best.23 In fact, HIV-infected women remain at a continued substantial risk for cervical neoplasia, even if they receive antiretroviral therapy.24 With the recent introduction of two human papillomavirus (HPV) vaccines, HPV types distribution and seroprevalence data among geographic and biological subgroups has become increasingly important, as the effectiveness of these vaccines in curbing the incidence of cervical cancer will be dependent, in large part, upon the prevalence of oncogenic vaccine types (HPV 16 and 18) in a given population. Previous results showed that naturally occurring serum antibodies to HPV 16, 18, VLPs are not associated with protection against detection of new infections with the homologous HPV types.25 As vaccination elicits much stronger antibody responses than natural infection,26 it is possible that HIV-infected women may still benefit from the available HPV vaccines. Results from a study conducted with HIV-infected men showed that the quadrivalent HPV vaccine elicited anti-HPV antibodies in a high proportion of those men, with 95% or greater showing seroconversion for each of the HPV types included in the vaccine. For those with preexisting anti-HPV antibodies, the vaccine induced a marked increase in antibody concentrations.27 So far, there is no guidance in regards to the Public Health use of HPV vaccines in resource limited settings (RLS) and particularly for HIV-infected women. HIV-infected women are disproportionately affected by
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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HPV-related disease. HPV serology might give an indication of the types of HPV that women have been exposed to. Understanding the epidemiology of the HPV seroreactivity to HPV types 6, 11, 16 and 18 in HIV positive women from RLS might be relevant to vaccine implementation in these countries. The present study has some limitations. We measured serum antibodies once and thus could not examine the prevalence of persistent seropositivity. Another limitation is the possibility that women with seropositive and seronegative status differ in the risk of exposure to HPV. No data was available from study subjects about their sexual history, which is a prime determinant of HPV seropositivity. HPV vaccine studies for HIV-infected women are underway in Brazil. Although seroreactivity is an imperfect measure of past exposure to HPV, it remains the only tool available to determine cumulative past exposure, which is important to know when designing prophylactic vaccination strategies. In conclusion our data provide strong evidence that both HIV-infected and uninfected women may potentially benefit from HPV-vaccination, as only 4.7% and 1.1% of them, respectively had been exposed to all four HPV-vaccine types. Funding Funding was provided by Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA, and by IPEC-Fiocruz Rio de Janeiro, Brazil. Competing interests The authors declare no conflict of interests. Ethical approval Ethical approval was given by the Institute of Clinical Research IPEC/Fiocruz, Rio de Janeiro - Brazil, Institutional Review Board and CONEP under the reference No. 235/2009 and CAAE 00200.009.00008 respectively. Acknowledgements We would like to thank Suely Almeida de Carvalho and Karine Pec¸anha for the excellent technical support for the collection of the storage samples. References 1. Arrossi S, Sankaranarayanan R, Parkin DM. Incidence and mortality of cervical cancer in Latin America. Salud Publica Mex 2003;45(Suppl. 3):S306–14. 2. INCA. Estimativa 2010: Incidência do câncer no Brasil. Rio de Janeiro, Brazil: Instituto Nacional do Câncer, Ministério da Sáude; 2009. 3. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. 4. Lacey CJ, Lowndes CM, Shah KV. Burden and management of non cancerous HPV-related HPV related conditions: HPV-6/11 disease. Vaccine 2006;24(3): 533–41. 5. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423–8. 6. Shah KV, Viscidi RP, Alberg AJ, Helzlsouer KJ, Comstock GW. Antibodies to human papillomavirus 16 and subsequent in situ or invasive cancer of the cervix. Cancer Epidemiol Biomarkers Prev 1997;6(4):233–7.
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7. Sun XW, Ellerbrock TV, Lungu O, Chiasson MA, Bush TJ, Wright TCJ. Human papillomavirus infection in human immunodeficiency virus–seropositive women. Obstet Gynecol 1995;85:680–6. 8. Jit M, Vyse A, Borrow R, Pebody R, Soldan K, Miller E. Prevalence of human papillomavirus antibodies in young female subjects in England. Br J Cancer 2007;97:989–91. 9. Wang SS, Schiffman M, Shields TS, Herrero R, Hildesheim A, et al. Seroprevalence of human papillomavirus-16, -18, -31, and -45 in a population-based cohort of 10000 women in Costa Rica. Br J Cancer 2003;89(7):1248–54, 6. 10. Olsson SE, Villa LL, Costa RL, Petta CA, Andrade RP, et al. Induction of immune memory following administration of a prophylactic quadrivalent human papillomavirus (HPV) types 6/11/16/18 L1 virus-like particle (VLP) vaccine. Vaccine 2007;25(26):4931–9. 11. Giuliano AR, Palefsky JM, Goldstone S, Moreira Jr ED, Penny ME, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 2011;364:401–11. 12. Kemp TJ, Hildesheim A, Safaeian M, Dauner JG, Pan Y, et al. HPV16/18 L1 VLP vaccine induces cross-neutralizing antibodies that may mediate cross-protection. Vaccine 2011;29(11):2011–4. ˜ N, Villa LL, Barr 13. Perez G, Lazcano-Ponce E, Hernandez-Avila M, García PJ, Munoz E, et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women. Int J Cancer 2008;122(6):1311–8. ˜ 14. Sun Y, Eluf-Neto J, Bosch FX, Munoz N, Walboomers JM, Meijer CJ, et al. Serum antibodies to human papillomavirus 16 proteins in women from Brazil with invasive cervical carcinoma. Cancer Epidemiol Biomarkers Prev 1999;8(10):935–40. 15. Rama CH, Roteli-Martins CM, Derchain SF, Oliveira EZ, et al. Serological detection of anti HPV 16/18 and its association with pap smear in adolescents and young women. Rev Assoc Med Bras 2006;52(1):43–7. 16. Firnhaber C, Evans D, Friedman-Khalili R, Willliams S, Michelow P, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected women from South Africa, Brazil and Botswana. J Clin Virol 2011;52(3):265–8. 17. Nonnenmacher B, Pintos J, Bozzetti MC, Mielzinska-Lohnas I, Lorincz AT, et al. Epidemiologic correlates of antibody response to human papillomavirus among women at low risk of cervical cancer. Int J STD AIDS 2003;14(4): 258–65. 18. Schneider A, Hotz M, Gissmann L. Increased prevalence of human papillomavirus in the lower genital tract of pregnant women. Int J Cancer 1987;40: 198–201. 19. Rando RF, Lindheim S, Hasty L, Sedlacek TV, Woodland M, Eder C. Increased frequency of detection of human papillomavirus deoxyribonucleic acid in exfoliated cervical cells during pregnancy. Am J Obstet Gynecol 1989;161:50–5. 20. Brandão VCRAB, Lacerda HR, Silva NL, Ximenes RAA. Frequency and types of human papillomavirus among pregnant and non-pregnant women with human immunodeficiency virus infection in Recife determined by genotyping. Mem Inst Oswaldo Cruz 2009;104(5):755–63. 21. Hagensee ME, Slavinsky J, Gaffga CM, Suros J, Kissinger P, et al. Seroprevalence of human papillomavirus type 16 in pregnant women. Obstet Gynecol 1999;(5 Pt 1):653–8. 22. Rama CH, Villa LL, Pagliusi S, Andreoli MA, Costa MC, et al. Seroprevalence of human papillomavirus 6, 11, 16, and 18 in young primiparous women in Sao Paulo, Brazil. Int J Gynecol Cancer 2010;20(8):1405–10. 23. Heard I, Tassie JM, Kazatchkine MD, Orth G. Highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in HIV-seropositive women. AIDS 2002;16:1799–802. 24. Meys R, Gotch FM, Bunker CB. Human papillomavirus in the era of highly active antiretroviral therapy for human immunodeficiency virus: an immune reconstitution-associated disease? Br J Dermatol 2010;162:6–11. 25. Viscidi RP, Snyder B, Cu-Uvin S, Hogan JW, Clayman B, et al. Human papillomavirus capsid antibody response to natural infection and risk of subsequent HPV infection in HIV-positive and HIV-negative women. Cancer Epidemiol Biomarkers Prev 2005;14(1):283–8. 26. Mariani L, Venuti A. HPV vaccine: an overview of immune response, clinical protection, and new approaches for the future. Rev J Transl Med 2010;27(8):105. 27. Laukkanen P, Koskela P, Pukkala E, Dillner J, Laara E, et al. Time trends in incidence and prevalence of human papillomavirus type 6, 11 and 16 infections in Finland. J Gen Virol 2003;84:2105–9. 28. Lu B, Viscidi RP, Wu Y, Nyitray AG, Villa LL, et al. Seroprevalence of human papillomavirus (HPV) type 6 and 16 vary by anatomic site of HPV infection in men. Cancer Epidemiol Biomarkers Prev 2012;21(9):1542–6. 29. Lu B, Viscidi RP, Lee JH, Wu Y, Villa LL, et al. Human papillomavirus (HPV) 6, 11, 16, and 18 seroprevalence is associated with sexual practice and age: results from the multinational HPV Infection in Men Study (HIM Study). Cancer Epidemiol Biomarkers Prev 2011;20(5):990–1002.
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Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil A.F. Nicol a,∗ , B. Grinsztejn b , R.K. Friedman b , V.G. Veloso b , C.B. Cunha b , I. Georg b , J.H. Pilotto c , R.I. Moreira b , C.A.V. Castro b , B. Silver d , R.P. Viscidi d a
Laboratory of Interdisciplinary Medicine, Instituto Oswaldo Cruz - FIOCRUZ, Rio de Janeiro, Brazil Instituto de Pesquisa Clínica Evandro Chagas, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil c Hospital Geral de Nova Iguac¸u & Laboratório de AIDS e Imunologia Molecular/IOC, Fundac¸ão Oswaldo Cruz, Rio de Janeiro, Brazil d Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA b
a r t i c l e
i n f o
Article history: Received 5 December 2012 Received in revised form 4 February 2013 Accepted 8 February 2013 Keywords: HPV seroprevalence HIV/AIDS Pregnancy VLP Brazil Q vaccine
a b s t r a c t Background: Information on vaccine-type HPV seroprevalence is essential for vaccine strategies; however, limited data are available on past exposure to HPV-quadrivalent vaccine types in HIV-infected woman in Brazil. Objectives: To assess the seroprevalence for HPV types 6, 11, 16 and 18 in HIV-infected and uninfected women, from Rio de Janeiro, Brazil and to investigate potential associations with age and pregnancy status. Study-design: 1100-sera were tested by virus-like particle (VLPs)-based ELISA for antibodies to HPV types 16, 18, 6 and 11. Statistical analysis was carried out by STATA/SE 10.1 and comparisons among HIVinfected and HIV-uninfected women were assessed by Poisson regression models with robust variance. Results: HPV-6, 11, 16 and 18 seroprevalence was significantly higher among HIV-positive women (29.9%, 8.5%, 56.2% and 38.0%, respectively) compared to HIV-negative women (10.9%, 3.5%, 30.8% and 21.7%, respectively), when adjusted by age and pregnancy status. Overall, 69.4% of HIV-infected and 41.5% of HIV-uninfected women tested positive for any HPV quadrivalent vaccine type. However 4.7% and 1.1%, respectively, tested positive for all HPV vaccine type. In HIV-uninfected women who were pregnant, we found a higher HPV-11 seroprevalence (8.5% vs. 1.5%; P < 0.001) and a lower HPV 16 seroprevalence (22.6% vs. 34.2%; P = 0.010) compared to not pregnant women. HIV-uninfected women, aged 40 or more years old had a higher HPV 16 seroprevalence compared to women aged less than 40 years old. Conclusions: We did not observe a strong association between age and positive HPV antibodies nor an association between pregnancy and HPV seroprevalence. HPV seroprevalence was significantly higher among HIV-infected women compared to HIV negative women. In both populations the seroprevalence to all four HPV vaccine types was low suggesting that women may potentially benefit from the HPV vaccines. © 2013 Elsevier B.V. All rights reserved.
1. Background Cervical cancer continues to impose a significant health burden in low- and medium-resourced countries of Africa, Asia and Latin America.1 In Brazil, cervical cancer is the second most
∗ Corresponding author at: Laboratory Interdisciplinary of Medical Research – IOC/Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro, RJ, Brazil. Tel.: +55 21 3865 8133; fax: +55 21 2590 3495. E-mail addresses: nicol@ioc.fiocruz.br, [email protected] (A.F. Nicol), [email protected] (B. Grinsztejn), [email protected] (R.K. Friedman), [email protected] (V.G. Veloso), [email protected] (C.B. Cunha), ingebourg.georg@ipec.fiocruz.br (I. Georg), [email protected] (J.H. Pilotto), Ronaldo@fiocruz.br (R.I. Moreira), cavcastro@fiocruz.br (C.A.V. Castro), [email protected] (B. Silver), [email protected] (R.P. Viscidi).
common form of cancer among women and the fourth cause of death by cancer.2 Human papillomavirus (HPV) 16 and 18 account for approximately 70% of cervical cancer worldwide.3 Low risk HPV-6 and 11 types can cause more than 90% of cases of genital warts,4 which also impact on health services once it requires several consultations for its resolution. The majority of HPV infections are transient and clear within 2 years.5 HPV DNA testing mainly reflects current HPV infection status and is not a good measure of cumulative lifetime exposure to the virus. The serum antibody response to HPV virus-like particles (VLP), on the other hand, remains relatively stable over time, even after clearance of an HPV infection,6 and is therefore a candidate marker for cumulative HPV exposure, thus complementing HPV DNA detection. Several studies have consistently identified that HIV-infected women are at increased risk for HPV infection.7 Most of the studies
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Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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on HPV seroprevalence in HIV-infected women have been carried out in women from high-resource countries,8 with scarce data available from resource limited settings. Knowledge of the burden of past infection with these HPV types among HIV infected women from Brazil will allow rationale utilization of HPV vaccines in this population.
pregnancy status. Statistical significance was defined by a Pvalue less than 0.05. Variables were described as percentages and prevalence ratios. Data were analyzed using STATA/SE 10.1 software.
2. Objectives
The mean age of the women was 36.7 years (SD 11.0 years); HIV-infected women were older (37.7) than HIV-uninfected (35.7) women. Table 1 presents the HPV-vaccine types seroprevalence according to HIV serostatus and the prevalence ratio for each type and the combined HPV-vaccine types between HIV-infected and uninfected women adjusted for age and pregnancy. Overall, 69.4% of HIV-infected and 41.5% of HIV-uninfected women tested positive for any HPV quadrivalent vaccine type. However, only 4.7% and 1.1%, respectively, of HIV-infected and HIV-uninfected women, tested positive for all four HPV vaccine types. HPV-16 was the type with the highest seroprevalence in both HIV-infected (56.2%) and HIV-uninfected (30.8%) women. The seroprevalence for each individual type and for all HPV-vaccine types was higher among HIV+ compared to HIV-negative women, when adjusted for age and pregnancy status. Concomitant seropositivity for HPV-16 and HPV-18 was observed in 32.3% of HIV-infected and 15.7% of HIV-uninfected women (data not shown). Table 2 compares the HPV seroprevalence among HIV-infected women by site. Seroprevalences for each HPV type and for concomitant HPV-vaccine type were statistically significantly higher among HIV-infected women from HGNI (a very poor metropolitan area in Rio de Janeiro) compared to HIV-infected women from IPEC. HPV seroprevalence by pregnancy status in HIV-infected and -uninfected women are depicted in Table 3. In HIV-uninfected women, HPV 11 seroprevalence was significantly higher among pregnant compared to non pregnant women (8.5% vs. 1.5%; P < 0.001). The opposite was found for HPV 16, e.g., a significantly lower seroprevalence among pregnant (22.6%) compared to non-pregnant (34.2%) HIV-uninfected women (P = 0.010). We did not find statistically significant differences in HPV seroprevalence according to pregnancy status in HIV-infected women. We did not observe statistically significant differences in adjusted models by age (data not shown). The HPV seroprevalence by age is depicted in Table 4. Among HIV-uninfected women, we found a statistically significant difference in age only for the HPV 16 seroprevalence outcome, e.g., women aged 40 or more years old presented a higher HPV 16 seroprevalence compared to women aged less than 40 years old (P = 0.020). Depicted in Table 5, are the few studies that evaluated HPV seroprevalence in Brazil. Higher HPV 16 seroprevalence was found among them, however different HPV seroprevalence was found according to the different stratifications and methods analyzed by the different studies.
The aim of the present study was to compare seroprevalence for HPV vaccine types 6, 11, 16 and 18 among HIV-infected and uninfected women, from Rio de Janeiro, Brazil and to investigate potential associations with age and pregnancy status. 3. Study design 3.1. Specimens A total of 1.100 serum stored samples collected between 2001 and 2008 from women under follow up at Institute of Clinical Research Evandro Chagas – IPEC/FIOCRUZ (N = 399), Hospital Geral de Nova Iguac¸u – HGNI (N = 134) and Dr Vasco Barcelos HIV Voluntary Counseling and Testing center (N = 568) were tested for HPV 6, 11, 16 and 18 antibodies; 532 (48.4%) samples were from HIVpositive (IPEC and HGNI) and 568 (51.6%) from HIV-negative (Dr Vasco Barcelos VCT) women. An age matched control criteria was used for selection of the HIV negative serum samples. Eighty-nine (16.7%) of the HIV-positive and 164 (28.9%) of the HIV-negative women were pregnant. 3.2. Assays Serum antibodies to HPV types 6, 11, 16, and 18 were measured by using VLP-based ELISA. HPV 6, 11, and 18 VLPs were produced in insect cells from recombinant baculoviruses expressing the L1 major capsid protein of individual HPV types, and HPV 16 VLPs were produced in mammalian cells from plasmids expressing the L1 and L2 capsid proteins. Specimens were tested in duplicate on separate plates, with retesting of specimens showing results exceeding a preset, acceptable coefficient of variation of 25%. Seropositivity was defined as an optical density (OD) value greater than the mean OD value plus 5 SDs, estimated by using serum samples from children of 1–10 years of age after exclusion of outliers. The cut-off point for HPV 6, 11, 16 and 18 was 0.200. 3.3. Statistical analysis Seroprevalence for each HPV-vaccine subtype (HPV-6, -11, 16 and -18) and for combined HPV-subtypes were calculated. Comparisons between HIV-infected and HIV-uninfected women (interest variable) were performed – controlling by age and pregnancy – using Poisson regression models with robust variance. Seroprevalence rates were compared according to sites, age and
4. Results
Table 1 HPV-vaccine type seroprevalence according HIV serostatus. Type
Total (N = 1100)
HIV(N = 568)
HIV+ (N = 532)
Unadjusted PR* (CI 95%)
Adjusted PR** (CI 95%)
HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type
221 (20.1) 65 (5.9) 474 (43.1) 325 (29.5) 31 (2.8) 605 (55.0)
62 (10.9) 20 (3.5) 175 (30.8) 123 (21.7) 6 (1.1) 236 (41.5)
159 (29.9) 45 (8.5) 299 (56.2) 202 (38.0) 25 (4.7) 369 (69.4)
2.7 (2.1–3.6) 2.4 (1.4–4.0) 1.8 (1.6–2.1) 1.8 (1.4–2.1) 4.4 (1.8–10.8) 1.7 (1.5–1.9)
2.7 (2.1–3.6) 2.7 (1.6–4.4) 1.8 (1.5–2.1) 1.8 (1.5–2.2) 4.8 (2.0–11.4) 1.7 (1.5–1.9)
* **
Unadjusted prevalence rate for “HIV serostatus: HIV-positive/HIV-negative” (reference: HIV-negative women). Adjusted prevalence rate for “HIV serostatus” controlled by age (reference: ≤30 years) and pregnancy status (reference: not pregnant).
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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Table 2 HPV seroprevalence by site of recruitment among HIV-positive women (N = 532). Type
Total (N = 532)
IPEC (N = 398)
HGNI (N = 134)
P-value
HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type
159 (29.9) 45 (8.5) 299 (56.2) 202 (38) 25 (4.7) 369 (69.4)
109 (27.4) 32 (8.0) 219 (55) 144 (36.2) 17 (4.3) 273 (68.6)
50 (37.3) 13 (9.7) 80 (59.7) 58 (43.3) 8 (6.0) 96 (71.6)
<0.001 <0.001 <0.001 <0.001 <0.001 <0.001
Table 3 HPV seroprevalence by pregnancy status in HIV negative and HIV positive women. Type
HPV 6 HPV 11 HPV 16* HPV 18 All HPV-vaccine type* Any HPV-vaccine type *
HIV-negative
HIV Positive
Not pregnant (N = 404)
Pregnant (N = 164)
P-value
Not pregnant (N = 443)
Pregnant (N = 89)
P-value
48 (11.9) 6 (1.5) 138 (34.2) 86 (21.3) 2 (0.5) 173 (42.8)
14 (8.5) 14 (8.5) 37 (22.6) 37 (22.6) 4 (2.4) 63 (38.4)
0.254 <0.001 0.010 0.738 0.064 0.343
129 (29.1) 36 (8.1) 248 (56.0) 163 (36.8) 19 (4.3) 308 (69.5)
30 (33.7) 9 (10.1) 51 (57.3) 39 (43.8) 6 (6.7) 61 (68.5)
0.379 0.537 0.817 0.197 0.319 0.855
Unadjusted model was presented, as we did not observe statistically difference when adjusted by age.
Table 4 HPV seroprevalence by age in HIV-negative and in HIV-positive women. Type
HIV negative women Total HPV 6 HPV 11* HPV 16** HPV 18 All HPV-vaccine type Any HPV-vaccine type HIV positive women Total HPV 6 HPV 11 HPV 16 HPV 18 All HPV-vaccine type Any HPV-vaccine type * **
Age
P-value
<30 years N (%)
30–39 years N (%)
40–49 years N (%)
≥ 50 years N (%)
160 16 (10) 13 (8.1) 39 (24.4) 40 (25) 4 (2.5) 66 (41.3)
205 19 (9.3) 3 (1.5) 57 (27.8) 37 (18.0) 1 (0.5) 77 (37.6)
145 19 (13.1) 2 (1.4) 58 (40.0) 37 (25.5) 1 (0.7) 67 (46.2)
58 8 (13.8) 2 (3.4) 21 (36.2) 9 (15.5) – 26 (44.8)
0.403 0.122 0.020 0.573 0.078 0.478
142 50 (35.2) 14 (9.9) 85 (59.9) 55 (38.7) 11 (7.7) 102 (71.8)
167 53 (31.7) 11 (6.6) 102 (61.1) 70 (41.9) 3 (1.8) 125 (74.9)
151 36 (23.8) 12 (7.9) 74 (49.0) 53 (35.1) 5 (3.3) 94 (62.3)
72 20 (27.8) 8 (11.1) 38 (52.8) 24 (33.3) 6 (8.3) 48 (66.7)
0.099 0.483 0.293 0.826 0.049 0.445
N (%)
Adjusted for pregnancy status, as we observed statistically difference for these variable and HPV 11. Unadjusted model was presented, as we did not observe statistically difference when adjusted by pregnancy status.
Table 5 HPV seroprevalence found on different Brazilians studies. Ref. Brazilian studies
Serology assay-type
Number of Brazilian serum assayed/total from the study
Stratification
HPV seroprevalence
Present study (2013)
VLP-based ELISA or HPV 6, 11, 16 and 18
1100/1100
Lu et al.28
VLP-based ELISA for HPV 16 Luminex Immuno Assay (HPV-4cLIA) for HPV 6, 11, 16 and 18 VLP-based ELISA for HPV 6, 11, 16 and 18
819/2.187
HIV infected and non infected women, pregnancy and age HIV neg. men baseline serostatus HIV infected women
HPV 6 (20.1%), HPV 11 (5.9%), HPV 16 (43.1%), HPV 18 (29.5%) HPV 16 (55%)
Firnhaber et al.16
Lu et al.29
Rama et al.22 Rama et al.15 Nonnenmacher et al.17
Sun et al.14
VLP-based ELISA for HPV 16 and 18 VLP-based ELISA for HPV 16 and 18 VLP-based ELISA-mixture antigen for HPV 6, 11, 16, 18 VLP-based ELISA for HPV 16
160/487
440/1477
HIV neg. men baseline serostatus
301/301
Primiparous young women
541/541
Adolescents and young health women Sexually active women
976/976
411/411
Invasive cervical cancer and controls
HPV 6 (46.9%), HPV 11 (21.9%), HPV 16 (29.4%), HPV 18 (18.1%) HPV 6 (19.5%), HPV 11 (25%), HPV 16 (16.1%), HPV 18 (10.5%) HPV 6 (5%), HPV 11 (2.7%), HPV 16 (9%), HPV 18 (7%) HPV 16 (14.60%), HPV 18 (6.46%) 32.7%
HPV 16 (47.4%),
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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5. Discussion Several studies have shown that immunization with HPV L1 VLPs is highly immunogenic and provides a high degree of protection against subsequent genital HPV infection, precancerous lesions, and cancers associated with vaccine-targeted genital HPV types.10–12 Limited data are available about HPV vaccine types 6, 11, 16 and 18 among HIV-infected, uninfected and pregnant women from Brazil. To our knowledge this is the first study that access and compare the seroprevalence of all 4 HPV types included in the quadrivalent vaccine according to HIV and pregnancy status and age in Brazil, thus providing data on past exposure to these HPV types that will be useful for vaccination strategy planning. A large Latin America study13 claimed that HPV seroprevalence in Latin American females is among the highest in the world (25%). In fact our study revealed an even higher overall HPV 6, 11, 16 and 18 seroprevalence; we detected a seroprevalence of 55% for any HPV type and 2.8% for all HPV vaccine types. Overall HPV 16 was the most prevalent type (43.1%), followed by HPV 18 (29.5%), HPV 6 (20.1%) and HPV 11 (5.9%). In a serological case–control study of invasive cervical cancer in Brazil the seroprevalence in controls was 24.4%.14 A serological study conducted in São Paulo, Brazil, in 2006 found a lower prevalence for HPV 16 (14.6%) and HPV 18 (6.4%) compared with our results.15 In our study, HPV seroprevalence for each and for all 4 HPVvaccine types was higher among HIV-infected compared with HIV-uninfected women. Our findings are in agreement with previous studies that reported higher HPV seroprevalence among HIV-infected women.7,9 In a study16 including 487 HIV-infected women from South Africa (N = 157) Botswana (N = 170) and Brazil (N = 160) using the Luminex Immuno Assay (HPV-4cLIA) for HPV 6, 11, 16 and 18, a higher overall seroprevalence, (approximately 65% to any one of the 4 HPV-vaccine types), was found compared to our results (55%). The seroprevalence to the individual HPV types differed from our findings, specially for the higher seroprevalence to HPV 6 and 11 in the former study. The differences may be attributed to subject selection, small sample size or more likely to differences in the assay methodology. We used a direct ELISA and the Firnhaber et al. study used a competitive inhibition assay with type specific monoclonal antibodies. Despite the fact that 69.4% and 41.5% of HIV-infected and noninfected women, respectively, were seropositive for at least one of the 4 HPV-types, only 4.7% and 1.1% of them were seropositive for all 4 HPV types. Thus only a small proportion of the women in our study had serological evidence of exposure to all 4 types included in the quadrivalent vaccine. Therefore those women who are at risk of HPV infection may benefit from vaccination, although the value of serostatus as a predictor of vaccine efficacy is still unknown at present. In the present study we found statistically significant difference in seroprevalence by site, which is most likely due to differences in past sexual behavior of the women sampled at the two sites. Lifetime number of sexual partners and earlier age of initiation of sexual intercourse are among the strongest determinants of HPV seroreactivity. Unfortunately no sexual history was obtained from study subjects; however, the HGNI site, which had the highest seroprevalence, recruited women from a poor metropolitan area of Rio de Janeiro and lower socioeconomic status is often associated with earlier age of onset of sexual activity and a greater lifetime number of sexual partners. In our study, pregnancy status and age did not modify the HPV seroprevalence, except for HPV 11 and for concomitant seropositivity for all 4 HPV-subtypes. The HPV 16 seroprevalence was higher in HIV negative women over 40 years of age compared to those less than 40 years of age. Among the HIV positive woman,
seroprevalence to all 4 HPV types was higher in women <30 years of age and >50 years of age compared to women 30–49 years of age; however, the number of subjects were small and the difference was of borderline significance. This suggests that young HIV-positive subjects are able to develop a long-lasting protective immunoresponse, reinforcing the concept that in women most genital tract HPV infections are transient, but most seroconversions are persistent.17 Although the incidence of HPV was increased over the course of pregnancy in some studies,18–20 the role of pregnancy in increasing the risk of HPV infection remains unclear. During the gestational period, a reduction in immunity and an imbalance in the vaginal flora may increase the risk of HPV infection. In the first trimester, the low immune response to HPV is associated with a higher persistence of HPV, which may clear during the third trimester with the recovery of immune response.21 Several studies have associated HPV seropositiity with age. We observed a trend of increasing seroprevalence with increasing age (>30 years old), with no statistically significant differences in seroprevalence by age, except for HPV 11 and 16 in HIV negative women. A recent serological study carried out in Brazil22 with young primiparous women found that 19.3% (N = 301) had antibodies to any of the 4 VLPs tested and seroprevalence to HPV 16 was higher than that to HPV 18, 11 and 6. The mean age of women in the study was 20 years. Another study from Brazil17 found an overall HPV seroprevalence of 39% for HPV 16, 18, 11 and 6. The lower seroprevalence found in these studies, compared with our study could be partially explained by the younger age of the subjects, since in both studies the methodological assays were done by VLPs. In general VLP assays are considered specific based on good correlations with type specific DNA detection and type specific seroconversions to incident DNA detection as documented in the few studies that included serial measurements. However, in human studies due to the high rate of exposure to multiple HPV types, low level cross reactivity cannot be entirely excluded. Although the increased combined antiretroviral therapy delivery in middle and low income countries has greatly decreased the burden of several opportunistic infections, and AIDS-related conditions, the impact of the partial immune restoration induced by antiretroviral therapy on the natural history of HPV infection seems modest, at best.23 In fact, HIV-infected women remain at a continued substantial risk for cervical neoplasia, even if they receive antiretroviral therapy.24 With the recent introduction of two human papillomavirus (HPV) vaccines, HPV types distribution and seroprevalence data among geographic and biological subgroups has become increasingly important, as the effectiveness of these vaccines in curbing the incidence of cervical cancer will be dependent, in large part, upon the prevalence of oncogenic vaccine types (HPV 16 and 18) in a given population. Previous results showed that naturally occurring serum antibodies to HPV 16, 18, VLPs are not associated with protection against detection of new infections with the homologous HPV types.25 As vaccination elicits much stronger antibody responses than natural infection,26 it is possible that HIV-infected women may still benefit from the available HPV vaccines. Results from a study conducted with HIV-infected men showed that the quadrivalent HPV vaccine elicited anti-HPV antibodies in a high proportion of those men, with 95% or greater showing seroconversion for each of the HPV types included in the vaccine. For those with preexisting anti-HPV antibodies, the vaccine induced a marked increase in antibody concentrations.27 So far, there is no guidance in regards to the Public Health use of HPV vaccines in resource limited settings (RLS) and particularly for HIV-infected women. HIV-infected women are disproportionately affected by
Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007
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HPV-related disease. HPV serology might give an indication of the types of HPV that women have been exposed to. Understanding the epidemiology of the HPV seroreactivity to HPV types 6, 11, 16 and 18 in HIV positive women from RLS might be relevant to vaccine implementation in these countries. The present study has some limitations. We measured serum antibodies once and thus could not examine the prevalence of persistent seropositivity. Another limitation is the possibility that women with seropositive and seronegative status differ in the risk of exposure to HPV. No data was available from study subjects about their sexual history, which is a prime determinant of HPV seropositivity. HPV vaccine studies for HIV-infected women are underway in Brazil. Although seroreactivity is an imperfect measure of past exposure to HPV, it remains the only tool available to determine cumulative past exposure, which is important to know when designing prophylactic vaccination strategies. In conclusion our data provide strong evidence that both HIV-infected and uninfected women may potentially benefit from HPV-vaccination, as only 4.7% and 1.1% of them, respectively had been exposed to all four HPV-vaccine types. Funding Funding was provided by Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, USA, and by IPEC-Fiocruz Rio de Janeiro, Brazil. Competing interests The authors declare no conflict of interests. Ethical approval Ethical approval was given by the Institute of Clinical Research IPEC/Fiocruz, Rio de Janeiro - Brazil, Institutional Review Board and CONEP under the reference No. 235/2009 and CAAE 00200.009.00008 respectively. Acknowledgements We would like to thank Suely Almeida de Carvalho and Karine Pec¸anha for the excellent technical support for the collection of the storage samples. References 1. Arrossi S, Sankaranarayanan R, Parkin DM. Incidence and mortality of cervical cancer in Latin America. Salud Publica Mex 2003;45(Suppl. 3):S306–14. 2. INCA. Estimativa 2010: Incidência do câncer no Brasil. Rio de Janeiro, Brazil: Instituto Nacional do Câncer, Ministério da Sáude; 2009. 3. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 1999;189:12–9. 4. Lacey CJ, Lowndes CM, Shah KV. Burden and management of non cancerous HPV-related HPV related conditions: HPV-6/11 disease. Vaccine 2006;24(3): 533–41. 5. Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 1998;338:423–8. 6. Shah KV, Viscidi RP, Alberg AJ, Helzlsouer KJ, Comstock GW. Antibodies to human papillomavirus 16 and subsequent in situ or invasive cancer of the cervix. Cancer Epidemiol Biomarkers Prev 1997;6(4):233–7.
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Please cite this article in press as: Nicol AF, et al. Seroprevalence of HPV vaccine types 6, 11, 16 and 18 in HIV-infected and uninfected women from Brazil. J Clin Virol (2013), http://dx.doi.org/10.1016/j.jcv.2013.02.007