Human Papillomavirus Serology Among Women Living With HIV: Type-Specific Seroprevalence, Seroconversion, and Risk of Cervical Reinfection

Human Papillomavirus Serology Among Women Living With HIV: Type-Specific Seroprevalence,... Abstract Background Human papillomavirus (HPV) serodynamics following infection has never been evaluated prospectively among women living with HIV (WLHIV). We determined HPV seroprevalence, seroconversion, and cervical HPV-DNA acquisition among WLHIV. Methods Prospective study of 604 WLHIV in Johannesburg, South Africa aged 25–50 years. At baseline and 16 months (endline), HPV type-specific antibodies (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) were measured using HPV-pseudovirions and cervical HPV-DNA genotypes using INNO-LiPA. Results Seroprevalence of any-HPV was 93.2% and simultaneous seropositivity for HPV types of the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 21.4%, 10.9%, and 2.8%. Among 219 women with cervical HPV-DNA, same-type seronegative and without high-grade cervical intraepithelial neoplasia at baseline, 51 (23.3%) had type-specific seroconversion at endline. Risk of type-specific seroconversion was higher among recent antiretroviral therapy users (ART ≤2 years vs ART naive: adjusted OR [aOR] = 2.39; 95% CI, 1.02–5.62), and lower among women with low CD4+ at endline (≤350 vs >350 cells/mm3: aOR = 0.51; 95% CI, 0.24–1.07). Risk of cervical HPV-DNA acquisition was lower in women seropositive for HPV18, 35, and 58 at baseline. Conclusion WLHIV have evidence of seroconversion in response to baseline HPV-DNA, dependent on CD4+ count and ART. Baseline HPV seropositivity confers limited protection against some HPV types. human papillomavirus, HPV, serology, antibodies, HIV, Africa As women living with human immunodeficiency virus (WLHIV) are experiencing longer life expectancy due to increased availability of antiretroviral therapy (ART), many remain at high risk of infection with human papillomavirus (HPV), acquiring anogenital warts, and progressing to cervical and other genital cancers. Primary prevention of HPV through vaccination can reduce the burden of disease and on screening and treatment services. The bivalent and quadrivalent HPV vaccines target 2 high-risk (HR)-HPV types (HPV16 and 18) responsible for about 70% of cervical cancers [1], whereas the nonavalent vaccine protects against a wider range of HR-HPV types (HPV16/18/31/33/45/52/58), as well as types causing anogenital warts (HPV6/11) and is estimated to prevent up to 90% of cervical cancers in women from the general population [1–3]. There is limited evidence of the serological response to HPV infection among WLHIV. The evidence regarding protection against reinfection for the same HPV type induced after natural infection is also unclear. A recent meta-analysis of 14 studies among 24000 individuals (90% women) from Europe, North America, Latin America, Asia, and Australia investigating the potential protective effect of naturally acquired type-specific antibodies [4] reported 30%–35% protection against subsequent infection with HPV16 (pooled relative risk [RR] = 0.65; 95% confidence interval [CI], 0.50–0.80) and HPV18 (RR = 0.70; 95% CI, 0.43–0.98) among women in the general population. However, seropositivity to a wider range of HPV types and possible seroprotection following natural infection have not been evaluated among WLHIV. An improved understanding of HPV type-specific serological responses in such high-risk populations and their risk of both new infection and reinfection is needed to guide targeted HPV control efforts, including possible use of HPV vaccination. We conducted a large prospective study of cervical cancer screening in a cohort of WLHIV in Burkina Faso and South Africa (HARP, HPV in Africa Research Partnership) [5]. In this paper, among women enrolled in the HARP study in South Africa, we first evaluated HPV seroprevalence and concordance of HPV DNA with same-type seropositivity at baseline for 15 HPV genotypes. Second, among women without high-grade cervical intraepithelial neoplasia (CIN2+) at baseline, we evaluated the factors associated with HPV seroconversion following baseline HPV-DNA infection, and risk of incident HPV-DNA detection among women seropositive for same-type HPV at baseline. METHODOLOGY Study Population and Specimen Collection The HARP cohort study has been described in detail elsewhere [5]. In South Africa, women were recruited from HIV treatment centers and surrounding communities in Johannesburg, from December 2011 to October 2012. Inclusion criteria were being HIV-1 seropositive, aged 25–50 years, and resident in the city. Exclusion criteria were history of prior treatment for cervical cancer, previous hysterectomy, and being pregnant or less than 8 weeks postpartum. Eligible participants provided signed informed consent. Enrolment was stratified in a 2:1 ratio of ART users : ART naive. Participants were followed up every 6 months for CD4+ T-lymphocytes count and up to scheduled month 18 visit (endline) when procedures similar to baseline were repeated. Ethical approval was granted by the University of Witwatersrand, Johannesburg, and the London School of Hygiene and Tropical Medicine. Laboratory Testing HPV-DNA genotyping was performed at baseline and endline using the INNO-LiPA HPV genotyping Extra assay (Fujirebio, Courtaboeuf, France). Analysis of HPV DNA positivity was restricted to the 15 types covered by the serology assay (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) with HR-HPV being similarly defined with the following 12 types: HPV16/18/31/33/35/39/45/52/56/58/59/68 [6]. HPV antibodies were detected using a multiplexed binding assay, which uses pseudovirions (PsV) as antigens and detects HPV type-specific IgG antibodies (PsV-Luminex). Serology was performed for “carcinogenic/probable carcinogenic” types HPV16/18/31/33/35/39/45/52/56/58/59/68 (except the HR-HPV type 51) and the low-risk (LR) types HPV6/11/73, at Karolinska Institute, Stockholm, Sweden [7, 8]. Serum samples were analyzed in 1:50 and 1:150 dilutions. Cutoff values to define seropositivity were calculated independently for each HPV type by analyzing the mean fluorescence intensity unit (MFI) values obtained from a panel of 100 Swedish children’s sera (≤12 years old). The cutoff algorithm was as recommended by the global HPV LabNet (mean MFI value of a negative control serum panel plus 3 standard deviations) [9]. If this cutoff value was unreasonably low (less than 400 MFI), 400 MFI was used as cutoff to have a sensitivity and specificity similar to classical HPV enzyme-linked immunosorbent assays [10]. Statistical Analysis Cervical HPV DNA Status Women were considered “HPV-DNA positive” if positive by INNO-LiPA for any of the HPV types included in the serology assay, and “HPV-DNA negative” if negative for all of these types. HPV-DNA genotype-specific persistence was defined as being positive for the same type at baseline and endline visits. Type-specific clearance was defined as being positive for a specific type at enrolment and negative for that type at endline visit. Given that no woman was simultaneously infected by all 15 HPV types, all women were at risk of acquiring at least 1 HPV infection and all were included in the analysis of associations of baseline seropositivity with same-type HPV DNA incidence. HPV Serology Status HPV serology results are presented as binary results (positive and negative for a given type) based on the preassigned cutoff. Overall and type-specific or group (vaccine targets) HPV seroprevalence was defined as being seropositive for any/type-specific/grouped types respectively, among women with serology data at baseline. HPV type-specific seroconversion was defined as being HPV-DNA positive (ie, recently exposed) and same-type seronegative at baseline that became same-type seropositive at endline, irrespective of the DNA status at endline. We also analyzed type-specific seropersistence (having same-type detectable antibody at baseline and endline) and seroreversion (seropositive for a specific HPV type at baseline and seronegative for the same type at endline) among all women who were seropositive for any HPV type at baseline, irrespective of their cervical HPV-DNA status. Longitudinal analyses were restricted to women without prevalent CIN2+ at baseline, as the natural history of HPV infection and serology dynamics in women with CIN2+ would be difficult to interpret because many women had received ablative therapy. For comparison of HPV seropositivity among type-specific HPV-DNA-positive and DNA-negative WLHIV at baseline, prevalence ratios were obtained from logistic regression using marginal standardization to estimate prevalence ratios, and the delta method to estimate 95% CI [11]. Associations between HPV seroconversion and exposure variables were estimated with generalized estimating equations to account for seropositivity by multiple HPV types within women [12]. To explore associations of HPV seroconversion with HIV-related factors, prespecified analyses included stratification by ART duration (≤2 or >2 years) and CD4+ cell counts (≤350 or >350 cells/mm3) at baseline and endline, and HIV-1 viral suppression (plasma HIV-1 RNA <1000 or ≥1000 copies/mL) at baseline. Stable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate), and endline visits. Multivariable analyses were adjusted for sociodemographic and behavioral factors that were independently associated with HPV seroconversion. For associations of baseline seropositivity with HPV-DNA incidence, logistic regression was used to estimate odds ratios (OR) and 95% CI. Data were analyzed using Stata version 14 (Stata Statistical Software, Stata Corporation, College Station, TX). RESULTS Study Population A full description of HARP study participants has been published elsewhere [5]. Of the 623 WLHIV enrolled in South Africa, the median age at enrolment was 34 years (interquartile range [IQR]: 30–40), and median time in follow-up was 16 months (IQR: 15.6–16.8). In total, 604 (97.0%) WLHIV had valid results for both HPV serology and genotyping at baseline (Figure 1). Of these, 390 (64.6%) reported taking ART throughout the study period with a median duration of 3.4 years (IQR: 1.8–5.3) during follow-up, 42 (7.0%) initiated ART during follow-up, and 172 (28.5%) remained ART naive throughout the study. The median baseline CD4+ cell counts of ART users, ART initiators, and ART naive were 421 cells/mm3 (IQR: 285–580), 333 cells/mm3 (IQR: 260–403), and 475 cells/mm3 (IQR: 366–625), respectively. CD4+ cell counts change per year were +7 cells/mm3 (IQR: −55 to 89), +83 cells/mm3 (IQR: −33 to 205), and −36 cells/mm3 (IQR: −119 to 24) in the 3 groups, respectively. Figure 1. View largeDownload slide Study flowchart. aGiven that no woman was infected by all 15 human papillomavirus (HPV) types, all women were at risk of acquiring at least 1 HPV; bDNA positive for any 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73); cDNA negative for all 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73). Figure 1. View largeDownload slide Study flowchart. aGiven that no woman was infected by all 15 human papillomavirus (HPV) types, all women were at risk of acquiring at least 1 HPV; bDNA positive for any 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73); cDNA negative for all 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73). HPV Seroprevalence at Baseline Seroprevalence of any of 15 HPV types was 93.2% (95% CI, 90.9%–95.1%), of whom 89.9% (506/563) were seropositive for multiple types (Figure 2). The seroprevalence of any 12 HR-HPV type was 90.7% (95% CI, 88.1%–92.9%). Overall, almost all women (n = 591; 97.8%) were positive by either serology or DNA for any HPV, and 583 (96.5%) for any HR-HPV types. Figure 2. View largeDownload slide Human papillomavirus (HPV) type seroprevalence and DNA prevalence among 604 women living with human immunodeficiency virus (HIV) in Johannesburg, South Africa. A, Prevalence of combination of HPV types. B, Prevalence of individual HPV types. Abbreviations: Any HPV, type prevalence defined as positive for at least 1 HPV type (6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) at baseline; Any HR-HPV, positive for at least 1 HR type (16/18/31/33/35/39/45/52/56/58/59/68) at baseline; Any 9V, positive for any of HPV6/11/16/18/31/33/45/52/58; Any 9V-HR, positive for any of HPV16/18/31/33/45/52/58; Any 4V, positive for any of HPV6/11/16/18; Any 4V-LR, positive for any of HPV6/11; Any 2V, positive for any of HPV16/18; All 9V, positive for all of HPV6,11,16,18,31,33,45,52, and 58; All 9V-HR, positive for all of HPV16,18,31,33,45,52, and 58; All 4V, positive for all of HPV6,11,16, and 18; All 2V, positive for both HPV16 and 18; All 4V-LR, positive for both HPV6 and 11. Figure 2. View largeDownload slide Human papillomavirus (HPV) type seroprevalence and DNA prevalence among 604 women living with human immunodeficiency virus (HIV) in Johannesburg, South Africa. A, Prevalence of combination of HPV types. B, Prevalence of individual HPV types. Abbreviations: Any HPV, type prevalence defined as positive for at least 1 HPV type (6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) at baseline; Any HR-HPV, positive for at least 1 HR type (16/18/31/33/35/39/45/52/56/58/59/68) at baseline; Any 9V, positive for any of HPV6/11/16/18/31/33/45/52/58; Any 9V-HR, positive for any of HPV16/18/31/33/45/52/58; Any 4V, positive for any of HPV6/11/16/18; Any 4V-LR, positive for any of HPV6/11; Any 2V, positive for any of HPV16/18; All 9V, positive for all of HPV6,11,16,18,31,33,45,52, and 58; All 9V-HR, positive for all of HPV16,18,31,33,45,52, and 58; All 4V, positive for all of HPV6,11,16, and 18; All 2V, positive for both HPV16 and 18; All 4V-LR, positive for both HPV6 and 11. Seroprevalence was highest for HPV31 (59.6%), followed by HPV58 (54.8%) and HPV16 (43.1%) (Figure 2). The seroprevalence of any HPV genotypes included in the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), or nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 59.3%, 73.5%, and 87.6%, respectively. Simultaneous seropositivity for all HPV types included in the bivalent, quadrivalent, and nonavalent vaccines was 21.4%, 10.9%, and 2.8%, respectively. Correlation of HPV-DNA and Antibody-Specific Prevalence Of 472 women DNA positive for any of the 15 HPV types at baseline, 279 (59.1%) were seropositive for the same HPV type (range by type: 25.5% for HPV45 to 68.9% for HPV31; Table 1). The type-specific HPV seroprevalence was significantly higher among those with same-type DNA positive compared to same-type DNA negative for HPV31, HPV35, HPV39, HPV52, HPV58, and low-risk type HPV11. Table 1. Comparison of HPV Seropositivity Among Type-Specific HPV DNA-Positive and DNA-Negative Women Living With HIV (N = 604) at Baseline DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b Abbreviations: aPR, adjusted prevalence ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk. aHPV type seropositive among DNA positive for the same type. bAny type HPV seropositive among DNA negative for all types. caPR for type-specific seroprevalence if same-type DNA positive compared to DNA negative, adjusted for injectable contraception, HIV viral suppression (plasma HIV-1 RNA <1000 copies/mL) found to be associated with any HPV seroprevalence at baseline, and CIN2+ status. aPR in bold corresponds to findings which were significant in multivariate analysis. View Large Table 1. Comparison of HPV Seropositivity Among Type-Specific HPV DNA-Positive and DNA-Negative Women Living With HIV (N = 604) at Baseline DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b Abbreviations: aPR, adjusted prevalence ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk. aHPV type seropositive among DNA positive for the same type. bAny type HPV seropositive among DNA negative for all types. caPR for type-specific seroprevalence if same-type DNA positive compared to DNA negative, adjusted for injectable contraception, HIV viral suppression (plasma HIV-1 RNA <1000 copies/mL) found to be associated with any HPV seroprevalence at baseline, and CIN2+ status. aPR in bold corresponds to findings which were significant in multivariate analysis. View Large HPV Seroconversion and Association With DNA Persistence and Clearance Of all 451 women without CIN2+ at enrolment who were followed-up until endline, genotyping and serology data at baseline and endline were available for 433 (96.0%; Figure 1). There were 219 women who were HPV-DNA positive and same-type seronegative at baseline. Same-type seroconversion was observed for 23.3% (51/219), irrespective of DNA status during follow-up. When considering the total number of baseline infections as denominator (n = 326), there were 56 (17.2%) HPV seroconversion events (Table 2). Risk of type-specific seroconversion was highest for HPV31 (53.9%) and HPV33 (33.3%) and lowest for HPV18 (17.1%) and HPV16 (2.4%). Overall, risk of type-specific seroconversion was greater with same-type persistent DNA infection compared to cleared infection; irrespective of newly detected DNA during follow-up (Table 2; any HPV type seroconversion, 23.0% vs 15.1%; crude OR = 1.75; 95% CI, 0.95–3.24; adjusted OR [aOR] = 1.56; 95% CI, 0.78–3.13, adjusted for injectable contraception and CD4+ cell count at endline). Table 2. Type-Specific Seroconversion at 16 Months Among 219 Women Living With HIV Without CIN2+ at Baseline All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) Abbreviations: CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; Sero−, seronegative. aSeroconversion calculated among 219 women with DNA+/Sero− status at baseline representing 326 infections. bSeroconversion calculated among DNA+/Sero− at baseline and with type-specific persistence at endline. cSeroconversion calculated among DNA+/Sero− at baseline and type-specific clearance at endline. View Large Table 2. Type-Specific Seroconversion at 16 Months Among 219 Women Living With HIV Without CIN2+ at Baseline All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) Abbreviations: CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; Sero−, seronegative. aSeroconversion calculated among 219 women with DNA+/Sero− status at baseline representing 326 infections. bSeroconversion calculated among DNA+/Sero− at baseline and with type-specific persistence at endline. cSeroconversion calculated among DNA+/Sero− at baseline and type-specific clearance at endline. View Large HIV-Related Factors Associated With HPV Seroconversion When considering the number of baseline infections as denominator, the risk of HPV seroconversion was similar by baseline CD4+ count (Table 3) but lower with low endline CD4+ (≤350 vs >350 cells/mm3: 10.8% vs 19.4%; aOR = 0.51; 95% CI, 0.24–1.07, adjusted for injectable contraceptive use), and this association was significant among ART users only (≤350 vs >350 cells/mm3: 8.0% vs 26.3%; aOR = 0.25; 95% CI, 0.08–0.75). Table 3. HIV-Related Factors Associated With HPV Seroconversion at 16 Months Using 319 Events of DNA Positive/Same Type Seronegative at Baseline (Among 219 Women Living With HIV) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) Abbreviations: aOR, adjusted odds ratio using generalized estimating equation; ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus. aAssociations with HPV seroconversion were adjusted for injectable contraception use and CD4+ count at endline, which were found to be associated with any HPV type seropositivity in multivariate analysis (with exception of associations with ART at baseline when baseline CD4+ was used for adjustment). aOR in bold correspond to findings which were significant in multivariate analysis. bCD4+ count at baseline available for 317 events; CD4+ count at endline available for 284 events. cART adherence measure available for 171 events. dBaseline CD4+ count among participants who were taking ART at baseline. eEndline CD4+ count among participants who were taking ART throughout follow-up. fStable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate) and endline visits. gBaseline CD4+ among participants who were ART naive at baseline. hEndline CD4+ count among participants who were ART naive throughout follow-up. View Large Table 3. HIV-Related Factors Associated With HPV Seroconversion at 16 Months Using 319 Events of DNA Positive/Same Type Seronegative at Baseline (Among 219 Women Living With HIV) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) Abbreviations: aOR, adjusted odds ratio using generalized estimating equation; ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus. aAssociations with HPV seroconversion were adjusted for injectable contraception use and CD4+ count at endline, which were found to be associated with any HPV type seropositivity in multivariate analysis (with exception of associations with ART at baseline when baseline CD4+ was used for adjustment). aOR in bold correspond to findings which were significant in multivariate analysis. bCD4+ count at baseline available for 317 events; CD4+ count at endline available for 284 events. cART adherence measure available for 171 events. dBaseline CD4+ count among participants who were taking ART at baseline. eEndline CD4+ count among participants who were taking ART throughout follow-up. fStable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate) and endline visits. gBaseline CD4+ among participants who were ART naive at baseline. hEndline CD4+ count among participants who were ART naive throughout follow-up. View Large The highest risk of seroconversion was among short-duration ART users (≤2 years ART vs ART naive at endline: 24.6% vs 14.2%; aOR = 2.39; 95% CI, 1.02–5.62, adjusted for injectable contraceptive use and endline CD4+ cell count). HPV seroconversion was also more likely among women who reported high adherence to ART at baseline (60%–90% vs <60% adherence, 22.4% vs 7.1%; aOR = 8.93; 95% CI, 1.13–70.36). Newly Detected HPV DNA Over 16 Months According to Type-Specific Seropositivity at Baseline Among the 433 women with genotyping and serology data at both visits (Figure 1), 221 (51.0%) women had newly detected HPV-DNA at endline, with a total of 327 incident infections (Table 4). The risk of incident infection was lower among women who were same-type seropositive compared to seronegative at baseline for HPV18 (1.5% vs 6.4%; aOR = 0.14; 95% CI, 0.02–0.80, adjusted for baseline CD4+ cell count, ART status, and seropositivity for any type from same HPV phylogenetic family); HPV35 (4.1% vs 11.9%; aOR = 0.26; 95% CI, 0.10–0.68), and HPV58 (1.8% vs 5.4%; aOR = 0.19; 95% CI, 0.04–0.89). Conversely, the risk was higher among those with same-type baseline seropositivity for HPV45 (10.5% vs 4.0%) but the association did not persist following adjustment for seropositivity from same HPV phylogenetic family (aOR = 2.81; 95% CI, 0.87–9.04), although numbers were small. Table 4. Newly Detected HPV DNA Among 433 Women Living With HIV Without CIN2+, Measured Over 16 Months Follow-Up, Stratified by Same Type Seropositivity at Baseline aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; LR, low risk. aNumber of women negative for that type at baseline. bNumber of incident infections among women negative for that type at baseline. caOR for DNA incidence among same-type seropositive vs seronegative at baseline, adjusted for age, smoking, condom, vaginal washing, bacterial vaginosis, Chlamydia trachomatis, Trichomonas vaginalis, CD4 count, and antiretroviral therapy status at baseline as reported in [5] and for seropositivity for HPV type from same family group, ie, HPV16 DNA incidence adjusted seropositivity for types HPV31/33/35/52/58 (except for HPV56,6,11, and 73 due to small numbers). aOR in bold font correspond to findings which were significant in multivariate analysis. daOR for DNA incidence among seropersistent vs seroreverted at endline, adjusted for CD4+ at baseline only due to small numbers. eAll women at risk of acquiring a HPV infection (no woman infected by all types at baseline). fAll women with any HPV type seronegative and same type DNA negative at baseline. gAll women with any HPV type seropositive and same type DNA negative at baseline. View Large Table 4. Newly Detected HPV DNA Among 433 Women Living With HIV Without CIN2+, Measured Over 16 Months Follow-Up, Stratified by Same Type Seropositivity at Baseline aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; LR, low risk. aNumber of women negative for that type at baseline. bNumber of incident infections among women negative for that type at baseline. caOR for DNA incidence among same-type seropositive vs seronegative at baseline, adjusted for age, smoking, condom, vaginal washing, bacterial vaginosis, Chlamydia trachomatis, Trichomonas vaginalis, CD4 count, and antiretroviral therapy status at baseline as reported in [5] and for seropositivity for HPV type from same family group, ie, HPV16 DNA incidence adjusted seropositivity for types HPV31/33/35/52/58 (except for HPV56,6,11, and 73 due to small numbers). aOR in bold font correspond to findings which were significant in multivariate analysis. daOR for DNA incidence among seropersistent vs seroreverted at endline, adjusted for CD4+ at baseline only due to small numbers. eAll women at risk of acquiring a HPV infection (no woman infected by all types at baseline). fAll women with any HPV type seronegative and same type DNA negative at baseline. gAll women with any HPV type seropositive and same type DNA negative at baseline. View Large Among 403 women with detectable antibodies at baseline, 384 (95.3%) had the same type detected again at endline. HPV-DNA incidence was similar among women with seropersistence and seroreversion (Table 4). DISCUSSION This prospective study of serological dynamics for 15 HPV types among WLHIV found a very high seroprevalence at baseline, new-type seroconversion, and type-specific seropersistence 16 months later. In keeping with these findings, these women also had high prevalence, incidence, and persistence of HR-HPV-DNA, including multiple type infection [5]. To our knowledge, this is the first study to report HPV seroconversion in conjunction with HPV-DNA over time among WLHIV. We report a similar seroprevalence for types HPV6, 11, and 16, as reported elsewhere among WLHIV in South Africa [13] and the United States [14]. We found that the proportion of women who were seropositive for multiple HPV types was higher than the prevalence of multiple HPV-DNA infections at baseline, suggesting prior exposure to these types. Although the prevalence of antibodies to HPV vaccine types was high, the simultaneous seropositivity for all 9vHPV vaccine types was observed in a minority of women. After 16 months of follow-up, we report evidence of same-type seroconversion, which was higher among women with same-type persistence compared to cleared infection at endline. Seroconversion rates reported in this study are lower than those reported among HIV-negative women. A study among 588 HIV-negative HPV-unvaccinated women aged 18–20 years [15] reported seroconversion rates of 59.5%, 54.1%, and 68.8% for HPV16, HPV18, and HPV6, respectively within 18 months of detection of same-type incident infection, and was more likely among women with same-type persistent infection, as found in our study. Similarly, among 6528 women in Costa Rica [16] 21.7% of women with HPV-DNA at baseline had seroconversion for HPV16 over a median 6.4 years, and was higher among women with persistent compared to cleared infection. While there are no studies among WLHIV to make any comparison, seroconversion among 245 HIV-infected men who have sex with men (MSM) in the Netherlands following anal or penile HPV infection was 23% over 12 months [17], and 42% over 24 months among 281 HIV-infected MSM initiating ART in Switzerland [18]. Seroconversion in our study varied by HPV type, and was highest for HPV31 and lowest for HPV16. The type-specific seroconversion rates reflected the type-specific infection states at follow-up. The overall incident and persistent HPV-DNA was higher for HPV16 than for other types [19]. The lower seroconversion and subsequent increased risk of HPV16 incidence and persistence could be a result of its immune evasion mechanisms [20]. Seroconversion was more frequent among women with higher CD4+ cell count (>350 cells/mm3) at endline and this association was observed in the short-duration (≤2 years) ART users only. A study among 281 MSM initiating ART and followed for a median of 2 years [18] reported that those with lower nadir CD4+ cell count (<200 cells/mm3) at ART initiation had the highest seroconversion rates, compared to MSM initiating ART at higher CD4+ cell count (≥350 cells/mm3). It is possible that ART-related immune reconstitution during follow-up may have promoted seroconversion, and this was highest among men with the lowest CD4+ cell count, possibly because they had the greatest CD4+ cell count recovery. Although nadir CD4+ cell count was not available in our study, short-duration ART users at endline had a lower baseline CD4+ cell count compared to both the long-duration ART or ART-naive women (median CD4+ count of 324, 461, and 497 cells/mm3, respectively [5]). Although baseline CD4+ cell count was not associated with seroconversion, the subsequent increase in CD4+ cell count at endline through ART-initiated immune reconstitution (median CD4+ cell count among short-duration ART users increased by +103 cells/mm3; IQR: −13 to 196) may have stimulated seroconversion among the recent ART users in response to the high rate of HPV-DNA persistence reported in this cohort [5]. This is also supported by our findings of higher seroconversion rates among women with better ART adherence. An additional explanation for higher seroconversion among short-duration ART users is linked to the higher HPV-DNA prevalence, persistence, and lack of viral clearance in this group compared to prolonged ART users in this cohort [5]. It can be speculated that among recent ART initiators, immune reconstitution may have been not entirely effective to prevent persistence in the short term [5]. Our finding of an association of seroconversion with higher endline (but not baseline) CD4+ count in this study, may reflect the delay required for seroconversion to occur after infection, which might also be influenced by the initial state of immunosuppression. As seen in young HIV-negative women, HPV16 seroconversion occurred between 6 and 12 months after DNA detection [15]. In our study, the duration of HPV-DNA infection at baseline could not be determined. Women taking ART for a prolonged duration (>2 years) had a similar low seroconversion rate as ART-naive women. This may be because women on prolonged ART and strong immune recovery may have fewer prevalent and persistent infections [5], which would be required to trigger seroconversion. The more puzzling finding, however, is that ART-naive women in this study had as high rates of persistent HR-HPV infection as short-duration ART users, and their CD4+ cell count at either time point was not associated with seroconversion. Increases in HPV seropositivity by ART status have been shown to be independent of CD4+ count in other studies among MSM [18] and WLHIV [14]. No study has yet compared seroconversion among ART users and ART-naive women following natural infection, but vaccination studies among WLHIV have shown that, while seroconversion rates are similar among ART users and ART-naive women in the United States and Puerto Rico [21], HPV16 and HPV18 antibody titers were lower among ART-naive but comparable between HIV-negative and ART users [21]. These data suggest there may be some beneficial impact of ART in promoting seroconversion. We found evidence that HPV antibodies detected at baseline provided protection against DNA detection only for HPV18, 35, and 58, for which infection rates were lower. A recent meta-analysis, which assessed whether naturally acquired immunity conferred protection against subsequent infection by the same type [4], reported that HIV-negative women with antibodies against HPV16 and HPV18 had a modest 35% and 30% lower risk of subsequent infection, respectively, against the corresponding type. We found no protection conferred by HPV16 antibodies against HPV16 DNA detection in this study. Others have reported that HPV16 is better able to evade the host immune surveillance relative to other HPV types [22], which may explain its predominance in high-grade cervical lesions in HIV-positive and HIV-negative women [3]. A prospective study among 829 WLHIV risk matched with 413 HIV-negative women in the United States [23] reported no statistically significant difference in the risk of reinfection of any HR-HPV (HPV16/18/31/35/45) among women with same-type seropositivity compared to same-type seronegative at baseline over a median 4.5 years, with the exception of a reduced risk with HPV45. Other studies have evaluated whether HPV antibodies detected at 2 or more time points were associated with subsequent detection of same-type HPV-DNA among HIV-negative women. A prospective study with longitudinal serology measurements among 608 HIV-negative women seen at 6-month intervals for 3 years in the United States [24] reported a reduction in risk of subsequent HPV16 detection among women with a sustained high level of HPV16 antibody (seropositivity at 2 or more time points) and its phylogenetically related types (HPV31/33/58). HPV seropersistence in our study over 16 months was very high; however, there was limited evidence that WLHIV who had type-specific seropersistence had lower HPV-DNA detection compared to women with seroreversion at endline. This finding suggests that seroprevalence, seropersistence, and seroreversion are not good markers of protection against subsequent DNA detection. Given the limited evidence that natural immunity can protect against subsequent infection [4], a multivalent vaccine such as the nonavalent vaccine would be beneficial, given that 55% of WLHIV in this study had multiple HR-HPV infection at baseline, 18% had multiple persistent types at endline [19], and few women were simultaneously infected by all vaccine types. This study was constrained by a limited number of visits between baseline and endline and the overall relatively short follow-up duration. Therefore, we cannot establish whether the seroconversion event occurred in response to either an infection that persisted during follow-up or a baseline infection that cleared followed by new DNA detection of the same type. Moreover, when evaluating the risk of new DNA detection according to same-type seropositivity at baseline, we cannot exclude the possibility that the infection detected at 16 months was a reinfection or a recurrence of a latent undetected infection. However, infrequent condom use, presence of other sexually transmitted infection, or reproductive tract infections (including Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis), vaginal cleansing, and low CD4+ counts at enrolment were associated with new DNA detection (data not shown). These factors may point to behaviors or factors enhancing the risk of a new sexually acquired infection, or modifiers of vaginal biome or mucosal immunity that may enhance the possibility of reactivation of a latent HPV infection. Analysis of new DNA detection over 16 months according to type-specific positivity was constrained by the small numbers of individual genotype positivity. This study had several important strengths, including its longitudinal design, and the availability of serology and genotyping data at both time points. It is the first study to measure HPV serodynamics longitudinally among WLHIV. In conclusion, this study shows that WLHIV have high HPV seroprevalence and seropersistence of type-specific antibodies. We found evidence of seroconversion over 16 months that was dependent on CD4+ cell count at endline. The high HPV incidence and the limited evidence that naturally acquired antibodies protect against new DNA detection combined with the fact that even though WLHIV have multiple infections, few have been infected with all preventable infections, suggest that WLHIV could benefit from highly multivalent HPV vaccination. Studies, including mathematical modeling studies, assessing the efficacy and cost-effectiveness of nonavalent HPV vaccine, are warranted in this population. Notes Author contributions. Conceived and designed the study: P. M., S. D., H. W., J. D., H. K.; coordinated the study: H. K., A. C., S. D., P. M.; participant recruitment and management: A. C., S. D.; performed the lab testing: H. F., J. N.; analyzed the data: H. K., H. F.; wrote the first draft of the manuscript: H. K.; contributed to the writing of the manuscript: all; criteria for authorship read and met: all; agree with manuscript results and conclusions: all. Acknowledgments.  Contributing members of the HARP study group included: A. Chikandiwa, E. Cutler, S. Delany-Moretlwe, D. A. Lewis, M.P. Magooa, V. Maseko, P. Michelow, B. Muzah, T. Omar, A. Puren (Johannesburg, South Africa); F. Djigma, J. Drabo, O. Goumbri-Lompo, N. Meda, B. Sawadogo, J. Simporé, A. Yonli, S Zan (Ouagadougou, Burkina Faso); V. Costes, M.N. Didelot, S. Doutre, N. Leventoux, N. Nagot, J. Ngou, M. Segondy (Montpellier, France); and A. Devine, C. Gilham, L. Gibson, H. Kelly, R. Legood, P. Mayaud, H.A. Weiss (London, UK). The HARP Study Group also wishes to thank its International Scientific Advisory Group constituting Prof. C. Lacey (Chair, University of York, UK), Prof. Y. Qiao (Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Prof. M. Chirenje (University of Harare, Zimbabwe), and Prof. S. de Sanjosé (Institut Catala d’Oncologia, Barcelona, Spain); and the members of the HARP Endpoint Committee including T. Omar (Johannesburg, South Africa), O. Goumbri-Lompo (Ouagadougou, Burkina Faso), S. Doutre, N. Leventoux, V. Costes (Montpellier, France), and O. Clavero (Institut Catala d’Oncologia, Barcelona, Spain). Financial support. This work was supported by the European Commission 7th Framework Programme (grant number HEALTH-2010-F2-265396); and the UK Medical Research Council PHINDS scheme (grant number PH01/14-39). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Presented in part: 31th International Papillomavirus Conference, Cape Town, South Africa, abstract number 404, 28 February to 4 March 2017. References 1. de Sanjose S , Quint WG , Alemany L , et al. ; Retrospective International Survey and HPV Time Trends Study Group . 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Google Scholar PubMed 24. Ho GY , Studentsov Y , Hall CB , et al. Risk factors for subsequent cervicovaginal human papillomavirus (HPV) infection and the protective role of antibodies to HPV-16 virus-like particles . J Infect Dis 2002 ; 186 : 737 – 42 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Human Papillomavirus Serology Among Women Living With HIV: Type-Specific Seroprevalence, Seroconversion, and Risk of Cervical Reinfection

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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0022-1899
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1537-6613
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10.1093/infdis/jiy252
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Abstract

Abstract Background Human papillomavirus (HPV) serodynamics following infection has never been evaluated prospectively among women living with HIV (WLHIV). We determined HPV seroprevalence, seroconversion, and cervical HPV-DNA acquisition among WLHIV. Methods Prospective study of 604 WLHIV in Johannesburg, South Africa aged 25–50 years. At baseline and 16 months (endline), HPV type-specific antibodies (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) were measured using HPV-pseudovirions and cervical HPV-DNA genotypes using INNO-LiPA. Results Seroprevalence of any-HPV was 93.2% and simultaneous seropositivity for HPV types of the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 21.4%, 10.9%, and 2.8%. Among 219 women with cervical HPV-DNA, same-type seronegative and without high-grade cervical intraepithelial neoplasia at baseline, 51 (23.3%) had type-specific seroconversion at endline. Risk of type-specific seroconversion was higher among recent antiretroviral therapy users (ART ≤2 years vs ART naive: adjusted OR [aOR] = 2.39; 95% CI, 1.02–5.62), and lower among women with low CD4+ at endline (≤350 vs >350 cells/mm3: aOR = 0.51; 95% CI, 0.24–1.07). Risk of cervical HPV-DNA acquisition was lower in women seropositive for HPV18, 35, and 58 at baseline. Conclusion WLHIV have evidence of seroconversion in response to baseline HPV-DNA, dependent on CD4+ count and ART. Baseline HPV seropositivity confers limited protection against some HPV types. human papillomavirus, HPV, serology, antibodies, HIV, Africa As women living with human immunodeficiency virus (WLHIV) are experiencing longer life expectancy due to increased availability of antiretroviral therapy (ART), many remain at high risk of infection with human papillomavirus (HPV), acquiring anogenital warts, and progressing to cervical and other genital cancers. Primary prevention of HPV through vaccination can reduce the burden of disease and on screening and treatment services. The bivalent and quadrivalent HPV vaccines target 2 high-risk (HR)-HPV types (HPV16 and 18) responsible for about 70% of cervical cancers [1], whereas the nonavalent vaccine protects against a wider range of HR-HPV types (HPV16/18/31/33/45/52/58), as well as types causing anogenital warts (HPV6/11) and is estimated to prevent up to 90% of cervical cancers in women from the general population [1–3]. There is limited evidence of the serological response to HPV infection among WLHIV. The evidence regarding protection against reinfection for the same HPV type induced after natural infection is also unclear. A recent meta-analysis of 14 studies among 24000 individuals (90% women) from Europe, North America, Latin America, Asia, and Australia investigating the potential protective effect of naturally acquired type-specific antibodies [4] reported 30%–35% protection against subsequent infection with HPV16 (pooled relative risk [RR] = 0.65; 95% confidence interval [CI], 0.50–0.80) and HPV18 (RR = 0.70; 95% CI, 0.43–0.98) among women in the general population. However, seropositivity to a wider range of HPV types and possible seroprotection following natural infection have not been evaluated among WLHIV. An improved understanding of HPV type-specific serological responses in such high-risk populations and their risk of both new infection and reinfection is needed to guide targeted HPV control efforts, including possible use of HPV vaccination. We conducted a large prospective study of cervical cancer screening in a cohort of WLHIV in Burkina Faso and South Africa (HARP, HPV in Africa Research Partnership) [5]. In this paper, among women enrolled in the HARP study in South Africa, we first evaluated HPV seroprevalence and concordance of HPV DNA with same-type seropositivity at baseline for 15 HPV genotypes. Second, among women without high-grade cervical intraepithelial neoplasia (CIN2+) at baseline, we evaluated the factors associated with HPV seroconversion following baseline HPV-DNA infection, and risk of incident HPV-DNA detection among women seropositive for same-type HPV at baseline. METHODOLOGY Study Population and Specimen Collection The HARP cohort study has been described in detail elsewhere [5]. In South Africa, women were recruited from HIV treatment centers and surrounding communities in Johannesburg, from December 2011 to October 2012. Inclusion criteria were being HIV-1 seropositive, aged 25–50 years, and resident in the city. Exclusion criteria were history of prior treatment for cervical cancer, previous hysterectomy, and being pregnant or less than 8 weeks postpartum. Eligible participants provided signed informed consent. Enrolment was stratified in a 2:1 ratio of ART users : ART naive. Participants were followed up every 6 months for CD4+ T-lymphocytes count and up to scheduled month 18 visit (endline) when procedures similar to baseline were repeated. Ethical approval was granted by the University of Witwatersrand, Johannesburg, and the London School of Hygiene and Tropical Medicine. Laboratory Testing HPV-DNA genotyping was performed at baseline and endline using the INNO-LiPA HPV genotyping Extra assay (Fujirebio, Courtaboeuf, France). Analysis of HPV DNA positivity was restricted to the 15 types covered by the serology assay (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) with HR-HPV being similarly defined with the following 12 types: HPV16/18/31/33/35/39/45/52/56/58/59/68 [6]. HPV antibodies were detected using a multiplexed binding assay, which uses pseudovirions (PsV) as antigens and detects HPV type-specific IgG antibodies (PsV-Luminex). Serology was performed for “carcinogenic/probable carcinogenic” types HPV16/18/31/33/35/39/45/52/56/58/59/68 (except the HR-HPV type 51) and the low-risk (LR) types HPV6/11/73, at Karolinska Institute, Stockholm, Sweden [7, 8]. Serum samples were analyzed in 1:50 and 1:150 dilutions. Cutoff values to define seropositivity were calculated independently for each HPV type by analyzing the mean fluorescence intensity unit (MFI) values obtained from a panel of 100 Swedish children’s sera (≤12 years old). The cutoff algorithm was as recommended by the global HPV LabNet (mean MFI value of a negative control serum panel plus 3 standard deviations) [9]. If this cutoff value was unreasonably low (less than 400 MFI), 400 MFI was used as cutoff to have a sensitivity and specificity similar to classical HPV enzyme-linked immunosorbent assays [10]. Statistical Analysis Cervical HPV DNA Status Women were considered “HPV-DNA positive” if positive by INNO-LiPA for any of the HPV types included in the serology assay, and “HPV-DNA negative” if negative for all of these types. HPV-DNA genotype-specific persistence was defined as being positive for the same type at baseline and endline visits. Type-specific clearance was defined as being positive for a specific type at enrolment and negative for that type at endline visit. Given that no woman was simultaneously infected by all 15 HPV types, all women were at risk of acquiring at least 1 HPV infection and all were included in the analysis of associations of baseline seropositivity with same-type HPV DNA incidence. HPV Serology Status HPV serology results are presented as binary results (positive and negative for a given type) based on the preassigned cutoff. Overall and type-specific or group (vaccine targets) HPV seroprevalence was defined as being seropositive for any/type-specific/grouped types respectively, among women with serology data at baseline. HPV type-specific seroconversion was defined as being HPV-DNA positive (ie, recently exposed) and same-type seronegative at baseline that became same-type seropositive at endline, irrespective of the DNA status at endline. We also analyzed type-specific seropersistence (having same-type detectable antibody at baseline and endline) and seroreversion (seropositive for a specific HPV type at baseline and seronegative for the same type at endline) among all women who were seropositive for any HPV type at baseline, irrespective of their cervical HPV-DNA status. Longitudinal analyses were restricted to women without prevalent CIN2+ at baseline, as the natural history of HPV infection and serology dynamics in women with CIN2+ would be difficult to interpret because many women had received ablative therapy. For comparison of HPV seropositivity among type-specific HPV-DNA-positive and DNA-negative WLHIV at baseline, prevalence ratios were obtained from logistic regression using marginal standardization to estimate prevalence ratios, and the delta method to estimate 95% CI [11]. Associations between HPV seroconversion and exposure variables were estimated with generalized estimating equations to account for seropositivity by multiple HPV types within women [12]. To explore associations of HPV seroconversion with HIV-related factors, prespecified analyses included stratification by ART duration (≤2 or >2 years) and CD4+ cell counts (≤350 or >350 cells/mm3) at baseline and endline, and HIV-1 viral suppression (plasma HIV-1 RNA <1000 or ≥1000 copies/mL) at baseline. Stable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate), and endline visits. Multivariable analyses were adjusted for sociodemographic and behavioral factors that were independently associated with HPV seroconversion. For associations of baseline seropositivity with HPV-DNA incidence, logistic regression was used to estimate odds ratios (OR) and 95% CI. Data were analyzed using Stata version 14 (Stata Statistical Software, Stata Corporation, College Station, TX). RESULTS Study Population A full description of HARP study participants has been published elsewhere [5]. Of the 623 WLHIV enrolled in South Africa, the median age at enrolment was 34 years (interquartile range [IQR]: 30–40), and median time in follow-up was 16 months (IQR: 15.6–16.8). In total, 604 (97.0%) WLHIV had valid results for both HPV serology and genotyping at baseline (Figure 1). Of these, 390 (64.6%) reported taking ART throughout the study period with a median duration of 3.4 years (IQR: 1.8–5.3) during follow-up, 42 (7.0%) initiated ART during follow-up, and 172 (28.5%) remained ART naive throughout the study. The median baseline CD4+ cell counts of ART users, ART initiators, and ART naive were 421 cells/mm3 (IQR: 285–580), 333 cells/mm3 (IQR: 260–403), and 475 cells/mm3 (IQR: 366–625), respectively. CD4+ cell counts change per year were +7 cells/mm3 (IQR: −55 to 89), +83 cells/mm3 (IQR: −33 to 205), and −36 cells/mm3 (IQR: −119 to 24) in the 3 groups, respectively. Figure 1. View largeDownload slide Study flowchart. aGiven that no woman was infected by all 15 human papillomavirus (HPV) types, all women were at risk of acquiring at least 1 HPV; bDNA positive for any 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73); cDNA negative for all 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73). Figure 1. View largeDownload slide Study flowchart. aGiven that no woman was infected by all 15 human papillomavirus (HPV) types, all women were at risk of acquiring at least 1 HPV; bDNA positive for any 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73); cDNA negative for all 15 types (HPV6/11/16/18/31/33/35/39/45/52/56/58/59/68/73). HPV Seroprevalence at Baseline Seroprevalence of any of 15 HPV types was 93.2% (95% CI, 90.9%–95.1%), of whom 89.9% (506/563) were seropositive for multiple types (Figure 2). The seroprevalence of any 12 HR-HPV type was 90.7% (95% CI, 88.1%–92.9%). Overall, almost all women (n = 591; 97.8%) were positive by either serology or DNA for any HPV, and 583 (96.5%) for any HR-HPV types. Figure 2. View largeDownload slide Human papillomavirus (HPV) type seroprevalence and DNA prevalence among 604 women living with human immunodeficiency virus (HIV) in Johannesburg, South Africa. A, Prevalence of combination of HPV types. B, Prevalence of individual HPV types. Abbreviations: Any HPV, type prevalence defined as positive for at least 1 HPV type (6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) at baseline; Any HR-HPV, positive for at least 1 HR type (16/18/31/33/35/39/45/52/56/58/59/68) at baseline; Any 9V, positive for any of HPV6/11/16/18/31/33/45/52/58; Any 9V-HR, positive for any of HPV16/18/31/33/45/52/58; Any 4V, positive for any of HPV6/11/16/18; Any 4V-LR, positive for any of HPV6/11; Any 2V, positive for any of HPV16/18; All 9V, positive for all of HPV6,11,16,18,31,33,45,52, and 58; All 9V-HR, positive for all of HPV16,18,31,33,45,52, and 58; All 4V, positive for all of HPV6,11,16, and 18; All 2V, positive for both HPV16 and 18; All 4V-LR, positive for both HPV6 and 11. Figure 2. View largeDownload slide Human papillomavirus (HPV) type seroprevalence and DNA prevalence among 604 women living with human immunodeficiency virus (HIV) in Johannesburg, South Africa. A, Prevalence of combination of HPV types. B, Prevalence of individual HPV types. Abbreviations: Any HPV, type prevalence defined as positive for at least 1 HPV type (6/11/16/18/31/33/35/39/45/52/56/58/59/68/73) at baseline; Any HR-HPV, positive for at least 1 HR type (16/18/31/33/35/39/45/52/56/58/59/68) at baseline; Any 9V, positive for any of HPV6/11/16/18/31/33/45/52/58; Any 9V-HR, positive for any of HPV16/18/31/33/45/52/58; Any 4V, positive for any of HPV6/11/16/18; Any 4V-LR, positive for any of HPV6/11; Any 2V, positive for any of HPV16/18; All 9V, positive for all of HPV6,11,16,18,31,33,45,52, and 58; All 9V-HR, positive for all of HPV16,18,31,33,45,52, and 58; All 4V, positive for all of HPV6,11,16, and 18; All 2V, positive for both HPV16 and 18; All 4V-LR, positive for both HPV6 and 11. Seroprevalence was highest for HPV31 (59.6%), followed by HPV58 (54.8%) and HPV16 (43.1%) (Figure 2). The seroprevalence of any HPV genotypes included in the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18), or nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines were 59.3%, 73.5%, and 87.6%, respectively. Simultaneous seropositivity for all HPV types included in the bivalent, quadrivalent, and nonavalent vaccines was 21.4%, 10.9%, and 2.8%, respectively. Correlation of HPV-DNA and Antibody-Specific Prevalence Of 472 women DNA positive for any of the 15 HPV types at baseline, 279 (59.1%) were seropositive for the same HPV type (range by type: 25.5% for HPV45 to 68.9% for HPV31; Table 1). The type-specific HPV seroprevalence was significantly higher among those with same-type DNA positive compared to same-type DNA negative for HPV31, HPV35, HPV39, HPV52, HPV58, and low-risk type HPV11. Table 1. Comparison of HPV Seropositivity Among Type-Specific HPV DNA-Positive and DNA-Negative Women Living With HIV (N = 604) at Baseline DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b Abbreviations: aPR, adjusted prevalence ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk. aHPV type seropositive among DNA positive for the same type. bAny type HPV seropositive among DNA negative for all types. caPR for type-specific seroprevalence if same-type DNA positive compared to DNA negative, adjusted for injectable contraception, HIV viral suppression (plasma HIV-1 RNA <1000 copies/mL) found to be associated with any HPV seroprevalence at baseline, and CIN2+ status. aPR in bold corresponds to findings which were significant in multivariate analysis. View Large Table 1. Comparison of HPV Seropositivity Among Type-Specific HPV DNA-Positive and DNA-Negative Women Living With HIV (N = 604) at Baseline DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b DNA Positive Seropositive Seropositive/DNA Positive DNA Negative Seropositive Seropositive/ DNA Negative aPR (95% CI)c (N) (n) (%) (N) (n) (%) Bi-/quadrivalent types HPV6 33 14 42.4 571 241 42.2 0.94 (0.60–1.49) HPV11 33 19 57.6 571 197 34.5 1.71 (1.24–2.35) HPV16 115 50 43.5 489 210 42.9 1.02 (0.80–1.31) HPV18 89 34 38.2 515 193 37.5 1.10 (0.83–1.47) Additional nonavalent types HPV31 61 42 68.9 543 318 58.6 1.28 (1.08–1.52) HPV33 48 25 52.1 556 219 39.4 1.25 (0.91–1.71) HPV45 47 12 25.5 557 107 19.2 1.42 (0.84–2.42) HPV52 146 60 41.1 458 129 28.2 1.54 (1.19–1.98) HPV58 54 36 66.7 550 295 53.6 1.27 (1.03–1.55) Nonvaccine types HPV35 99 59 59.6 505 197 39.0 1.52 (1.23–1.88) HPV39 48 25 52.1 556 199 35.8 1.46 (1.08–1.98) HPV56 58 20 34.5 546 183 33.5 1.01 (0.68–1.49) HPV59 11 6 54.5 593 201 33.9 1.59 (0.90–2.79) HPV68 33 12 36.4 571 166 29.1 1.33 (0.82–2.14) HPV73 10 4 40.0 594 130 21.9 1.15 (0.35–3.74) Any HPVa,b 472 279 59.1a 132 119 90.2b Any HR-HPVa,b 456 267 58.6a 148 127 85.8b Abbreviations: aPR, adjusted prevalence ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk. aHPV type seropositive among DNA positive for the same type. bAny type HPV seropositive among DNA negative for all types. caPR for type-specific seroprevalence if same-type DNA positive compared to DNA negative, adjusted for injectable contraception, HIV viral suppression (plasma HIV-1 RNA <1000 copies/mL) found to be associated with any HPV seroprevalence at baseline, and CIN2+ status. aPR in bold corresponds to findings which were significant in multivariate analysis. View Large HPV Seroconversion and Association With DNA Persistence and Clearance Of all 451 women without CIN2+ at enrolment who were followed-up until endline, genotyping and serology data at baseline and endline were available for 433 (96.0%; Figure 1). There were 219 women who were HPV-DNA positive and same-type seronegative at baseline. Same-type seroconversion was observed for 23.3% (51/219), irrespective of DNA status during follow-up. When considering the total number of baseline infections as denominator (n = 326), there were 56 (17.2%) HPV seroconversion events (Table 2). Risk of type-specific seroconversion was highest for HPV31 (53.9%) and HPV33 (33.3%) and lowest for HPV18 (17.1%) and HPV16 (2.4%). Overall, risk of type-specific seroconversion was greater with same-type persistent DNA infection compared to cleared infection; irrespective of newly detected DNA during follow-up (Table 2; any HPV type seroconversion, 23.0% vs 15.1%; crude OR = 1.75; 95% CI, 0.95–3.24; adjusted OR [aOR] = 1.56; 95% CI, 0.78–3.13, adjusted for injectable contraception and CD4+ cell count at endline). Table 2. Type-Specific Seroconversion at 16 Months Among 219 Women Living With HIV Without CIN2+ at Baseline All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) Abbreviations: CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; Sero−, seronegative. aSeroconversion calculated among 219 women with DNA+/Sero− status at baseline representing 326 infections. bSeroconversion calculated among DNA+/Sero− at baseline and with type-specific persistence at endline. cSeroconversion calculated among DNA+/Sero− at baseline and type-specific clearance at endline. View Large Table 2. Type-Specific Seroconversion at 16 Months Among 219 Women Living With HIV Without CIN2+ at Baseline All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) All Participantsa Participants With HPV DNA Persistenceb Participants With HPV DNA Clearancec DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events DNA+ and Sero− at Baseline Seroconversion Events N Infections n (%)a N Infections n (%)b N Infections n (%)c HPV16 41 1 (2.4) 11 1 (9.1) 30 0 (0.0) HPV18 41 7 (17.1) 14 3 (21.4) 27 4 (14.8) HPV6 13 3 (23.1) 0 0 (0.0) 13 3 (23.1) HPV11 13 2 (15.4) 3 1 (33.3) 10 1 (10.0) HPV31 13 7 (53.9) 2 2 (100.0) 11 5 (45.5) HPV33 15 5 (33.3) 1 1 (100.0) 14 4 (28.6) HPV45 25 4 (16.0) 8 1 (12.5) 17 3 (17.6) HPV52 63 12 (19.1) 21 6 (28.6) 42 6 (14.3) HPV58 12 3 (25.0) 4 1 (25.0) 8 2 (25.0) HPV35 26 6 (23.1) 11 3 (27.3) 15 3 (20.0) HPV39 19 0 (0.0) 2 0 (0.0) 17 0 (0.0) HPV56 26 4 (15.4) 4 1 (25.0) 22 3 (13.6) HPV59 4 1 (25.0) 1 0 (0.0) 3 1 (33.3) HPV68 13 1 (7.7) 3 0 (0.0) 10 1 (10.0) HPV73 2 0 (0.0) 2 0 (0.0) 0 0 (0.0) Any HPV 326 56 (17.2) 87 20 (23.0) 239 36 (15.1) Any HR-HPV 298 51 (17.1) 82 19 (23.2) 216 32 (14.8) Abbreviations: CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; Sero−, seronegative. aSeroconversion calculated among 219 women with DNA+/Sero− status at baseline representing 326 infections. bSeroconversion calculated among DNA+/Sero− at baseline and with type-specific persistence at endline. cSeroconversion calculated among DNA+/Sero− at baseline and type-specific clearance at endline. View Large HIV-Related Factors Associated With HPV Seroconversion When considering the number of baseline infections as denominator, the risk of HPV seroconversion was similar by baseline CD4+ count (Table 3) but lower with low endline CD4+ (≤350 vs >350 cells/mm3: 10.8% vs 19.4%; aOR = 0.51; 95% CI, 0.24–1.07, adjusted for injectable contraceptive use), and this association was significant among ART users only (≤350 vs >350 cells/mm3: 8.0% vs 26.3%; aOR = 0.25; 95% CI, 0.08–0.75). Table 3. HIV-Related Factors Associated With HPV Seroconversion at 16 Months Using 319 Events of DNA Positive/Same Type Seronegative at Baseline (Among 219 Women Living With HIV) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) Abbreviations: aOR, adjusted odds ratio using generalized estimating equation; ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus. aAssociations with HPV seroconversion were adjusted for injectable contraception use and CD4+ count at endline, which were found to be associated with any HPV type seropositivity in multivariate analysis (with exception of associations with ART at baseline when baseline CD4+ was used for adjustment). aOR in bold correspond to findings which were significant in multivariate analysis. bCD4+ count at baseline available for 317 events; CD4+ count at endline available for 284 events. cART adherence measure available for 171 events. dBaseline CD4+ count among participants who were taking ART at baseline. eEndline CD4+ count among participants who were taking ART throughout follow-up. fStable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate) and endline visits. gBaseline CD4+ among participants who were ART naive at baseline. hEndline CD4+ count among participants who were ART naive throughout follow-up. View Large Table 3. HIV-Related Factors Associated With HPV Seroconversion at 16 Months Using 319 Events of DNA Positive/Same Type Seronegative at Baseline (Among 219 Women Living With HIV) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) N n (%) aOR (95% CI)a All women Baseline CD4+ count (cells/mm3)b  ≤350 96 19 (19.8) 1.19 (0.64–2.21)  >350 221 37 (16.7) 1.00 Endline CD4+ count (cells/mm3)b  ≤350 93 10 (10.8) 0.51 (0.24–1.07)  >350 191 37 (19.4) 1.00 ART status at endline  ART > 2 years 124 22 (17.7) 1.77 (0.85–3.69)  ART ≤ 2 years 61 15 (24.6) 2.39 (1.02–5.62)  ART naive 134 19 (14.2) 1.00 Baseline ART users HIV-1 viral suppression at baseline  <1000 copies/mL 146 27 (18.5) 1.00  ≥1000 copies/mL 26 7 (26.9) 1.91 (0.67–5.38) ART adherence at baselinec  Low adherence (<60%) 28 2 (7.1) 1.00  Moderate adherence (60%–90%) 143 32 (22.4) 8.93 (1.13–70.36) Baseline CD4+ count (cells/mm3)d  ≤350 64 15 (23.4) 1.38 (0.64–2.96)  >350 106 19 (17.9) 1.00 Endline CD4+ count (cells/mm3)e  ≤350 50 4 (8.0) 0.25 (0.08–0.75)  >350 99 26 (26.3) 1.00 Stable high CD4+ countf  Yes 27 4 (14.8) 1.00  No 144 30 (20.8) 1.52 (0.49–4.74) ART naive women Baseline CD4+ count (cells/mm3)g  ≤350 32 4 (12.5) 0.71 (0.22–2.31)  >350 115 18 (15.7) 1.00 Endline CD4+ count (cells/mm3)h  ≤350 40 6 (15.0) 1.40 (0.46–4.30)  >350 81 9 (11.1) 1.00 Stable high CD4+ countf  Yes 27 1 (3.7) 1.00  No 121 21 (17.4) 5.18 (0.66–40.85) Abbreviations: aOR, adjusted odds ratio using generalized estimating equation; ART, antiretroviral therapy; CI, confidence interval; HIV, human immunodeficiency virus; HPV, human papillomavirus. aAssociations with HPV seroconversion were adjusted for injectable contraception use and CD4+ count at endline, which were found to be associated with any HPV type seropositivity in multivariate analysis (with exception of associations with ART at baseline when baseline CD4+ was used for adjustment). aOR in bold correspond to findings which were significant in multivariate analysis. bCD4+ count at baseline available for 317 events; CD4+ count at endline available for 284 events. cART adherence measure available for 171 events. dBaseline CD4+ count among participants who were taking ART at baseline. eEndline CD4+ count among participants who were taking ART throughout follow-up. fStable high CD4+ count was defined as having CD4+ counts >500 cells/mm3 at baseline, month 12 (intermediate) and endline visits. gBaseline CD4+ among participants who were ART naive at baseline. hEndline CD4+ count among participants who were ART naive throughout follow-up. View Large The highest risk of seroconversion was among short-duration ART users (≤2 years ART vs ART naive at endline: 24.6% vs 14.2%; aOR = 2.39; 95% CI, 1.02–5.62, adjusted for injectable contraceptive use and endline CD4+ cell count). HPV seroconversion was also more likely among women who reported high adherence to ART at baseline (60%–90% vs <60% adherence, 22.4% vs 7.1%; aOR = 8.93; 95% CI, 1.13–70.36). Newly Detected HPV DNA Over 16 Months According to Type-Specific Seropositivity at Baseline Among the 433 women with genotyping and serology data at both visits (Figure 1), 221 (51.0%) women had newly detected HPV-DNA at endline, with a total of 327 incident infections (Table 4). The risk of incident infection was lower among women who were same-type seropositive compared to seronegative at baseline for HPV18 (1.5% vs 6.4%; aOR = 0.14; 95% CI, 0.02–0.80, adjusted for baseline CD4+ cell count, ART status, and seropositivity for any type from same HPV phylogenetic family); HPV35 (4.1% vs 11.9%; aOR = 0.26; 95% CI, 0.10–0.68), and HPV58 (1.8% vs 5.4%; aOR = 0.19; 95% CI, 0.04–0.89). Conversely, the risk was higher among those with same-type baseline seropositivity for HPV45 (10.5% vs 4.0%) but the association did not persist following adjustment for seropositivity from same HPV phylogenetic family (aOR = 2.81; 95% CI, 0.87–9.04), although numbers were small. Table 4. Newly Detected HPV DNA Among 433 Women Living With HIV Without CIN2+, Measured Over 16 Months Follow-Up, Stratified by Same Type Seropositivity at Baseline aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; LR, low risk. aNumber of women negative for that type at baseline. bNumber of incident infections among women negative for that type at baseline. caOR for DNA incidence among same-type seropositive vs seronegative at baseline, adjusted for age, smoking, condom, vaginal washing, bacterial vaginosis, Chlamydia trachomatis, Trichomonas vaginalis, CD4 count, and antiretroviral therapy status at baseline as reported in [5] and for seropositivity for HPV type from same family group, ie, HPV16 DNA incidence adjusted seropositivity for types HPV31/33/35/52/58 (except for HPV56,6,11, and 73 due to small numbers). aOR in bold font correspond to findings which were significant in multivariate analysis. daOR for DNA incidence among seropersistent vs seroreverted at endline, adjusted for CD4+ at baseline only due to small numbers. eAll women at risk of acquiring a HPV infection (no woman infected by all types at baseline). fAll women with any HPV type seronegative and same type DNA negative at baseline. gAll women with any HPV type seropositive and same type DNA negative at baseline. View Large Table 4. Newly Detected HPV DNA Among 433 Women Living With HIV Without CIN2+, Measured Over 16 Months Follow-Up, Stratified by Same Type Seropositivity at Baseline aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) aOR (95%CI)c Among Seropositive at Baseline All Participants Seronegative at Baseline Seropositive at Baseline Seropersistence at Endline Seroreversion at Endline aOR (95% CI)d Na n (%)b Na n (%)b Na n (%)b Na n (%)b Na n (%)b Any alpha-9 HR-HPV types HPV16 366 48 (13.1) 203 25 (12.3) 163 23 (14.1) 1.48 (0.69–3.15) 135 20 (14.8) 28 3 (10.7) 1.50 (0.39–5.72) HPV31 394 20 (5.1) 169 8 (4.7) 225 12 (5.3) 1.12 (0.36–3.45) 204 10 (4.9) 21 2 (9.5) 0.57 (0.11–2.92) HPV33 408 17 (4.2) 248 11 (4.4) 160 6 (3.8) 0.70 (0.21–2.33) 143 5 (3.5) 17 1 (5.9) 0.59 (0.06–5.60) HPV35 374 33 (8.8) 227 27 (11.9) 147 6 (4.1) 0.26 (0.10–0.68) 110 4 (3.6) 37 2 (5.4) 0.67 (0.11–4.13) HPV52 327 55 (16.8) 233 41 (17.6) 94 14 (14.9) 0.77 (0.36–1.65) 82 12 (14.6) 12 2 (16.7) 0.78 (0.14–4.37) HPV58 404 14 (3.5) 187 10 (5.4) 217 4 (1.8) 0.19 (0.04–0.89) 191 3 (1.5) 26 1 (3.9) 0.29 (0.02–3.48) Any alpha-7 HR-HPV types HPV18 367 17 (4.6) 235 15 (6.4) 132 2 (1.5) 0.14 (0.02–0.80) 84 2 (2.4) 48 0 (0.0) HPV39 397 24 (6.1) 251 14 (5.6) 146 10 (6.9) 1.69 (0.65–4.42) 83 5 (6.0) 63 5 (7.9) 0.78 (0.21–2.85) HPV45 403 21 (5.2) 327 13 (4.0) 76 8 (10.5) 2.81 (0.87–9.04) 37 4 (10.8) 39 4 (10.3) 1.42 (0.27–7.66) HPV59 424 5 (1.2) 280 4 (1.4) 144 1 (0.7) 0.41 (0.02–8.74) 107 1 (0.9) 37 0 (0.0) HPV68 412 26 (6.3) 299 13 (4.4) 113 13 (11.5) 4.07 (1.52–10.90) 89 11 (12.4) 24 2 (8.3) 1.30 (0.26–6.60) Other HPV types HPV56 396 16 (4.0) 264 10 (3.8) 132 6 (4.6) 1.56 (0.51–4.76) 98 5 (5.1) 34 1 (2.9) 1.51 (0.17–13.76) LR-HPV types HPV6 410 13 (3.2) 241 7 (2.9) 169 6 (3.6) 1.28 (0.41–4.03) 142 5 (3.5) 27 1 (3.7) 1.09 (0.12–10.26) HPV11 408 15 (3.7) 269 10 (3.7) 139 5 (3.6) 1.16 (0.37–3.67) 119 4 (3.4) 20 1 (5.0) 0.73 (0.08–7.07) HPV73 428 3 (0.7) 331 1 (0.3) 97 2 (2.1) 28.03 (0.98–798.1) 72 1 (1.4) 25 1 (4.0) 0.40 (0.02–6.73) Any HPV 433e 327 427f 209 (48.9) 400g 118 (29.5) Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CIN2+, high-grade cervical intraepithelial neoplasia; HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk; LR, low risk. aNumber of women negative for that type at baseline. bNumber of incident infections among women negative for that type at baseline. caOR for DNA incidence among same-type seropositive vs seronegative at baseline, adjusted for age, smoking, condom, vaginal washing, bacterial vaginosis, Chlamydia trachomatis, Trichomonas vaginalis, CD4 count, and antiretroviral therapy status at baseline as reported in [5] and for seropositivity for HPV type from same family group, ie, HPV16 DNA incidence adjusted seropositivity for types HPV31/33/35/52/58 (except for HPV56,6,11, and 73 due to small numbers). aOR in bold font correspond to findings which were significant in multivariate analysis. daOR for DNA incidence among seropersistent vs seroreverted at endline, adjusted for CD4+ at baseline only due to small numbers. eAll women at risk of acquiring a HPV infection (no woman infected by all types at baseline). fAll women with any HPV type seronegative and same type DNA negative at baseline. gAll women with any HPV type seropositive and same type DNA negative at baseline. View Large Among 403 women with detectable antibodies at baseline, 384 (95.3%) had the same type detected again at endline. HPV-DNA incidence was similar among women with seropersistence and seroreversion (Table 4). DISCUSSION This prospective study of serological dynamics for 15 HPV types among WLHIV found a very high seroprevalence at baseline, new-type seroconversion, and type-specific seropersistence 16 months later. In keeping with these findings, these women also had high prevalence, incidence, and persistence of HR-HPV-DNA, including multiple type infection [5]. To our knowledge, this is the first study to report HPV seroconversion in conjunction with HPV-DNA over time among WLHIV. We report a similar seroprevalence for types HPV6, 11, and 16, as reported elsewhere among WLHIV in South Africa [13] and the United States [14]. We found that the proportion of women who were seropositive for multiple HPV types was higher than the prevalence of multiple HPV-DNA infections at baseline, suggesting prior exposure to these types. Although the prevalence of antibodies to HPV vaccine types was high, the simultaneous seropositivity for all 9vHPV vaccine types was observed in a minority of women. After 16 months of follow-up, we report evidence of same-type seroconversion, which was higher among women with same-type persistence compared to cleared infection at endline. Seroconversion rates reported in this study are lower than those reported among HIV-negative women. A study among 588 HIV-negative HPV-unvaccinated women aged 18–20 years [15] reported seroconversion rates of 59.5%, 54.1%, and 68.8% for HPV16, HPV18, and HPV6, respectively within 18 months of detection of same-type incident infection, and was more likely among women with same-type persistent infection, as found in our study. Similarly, among 6528 women in Costa Rica [16] 21.7% of women with HPV-DNA at baseline had seroconversion for HPV16 over a median 6.4 years, and was higher among women with persistent compared to cleared infection. While there are no studies among WLHIV to make any comparison, seroconversion among 245 HIV-infected men who have sex with men (MSM) in the Netherlands following anal or penile HPV infection was 23% over 12 months [17], and 42% over 24 months among 281 HIV-infected MSM initiating ART in Switzerland [18]. Seroconversion in our study varied by HPV type, and was highest for HPV31 and lowest for HPV16. The type-specific seroconversion rates reflected the type-specific infection states at follow-up. The overall incident and persistent HPV-DNA was higher for HPV16 than for other types [19]. The lower seroconversion and subsequent increased risk of HPV16 incidence and persistence could be a result of its immune evasion mechanisms [20]. Seroconversion was more frequent among women with higher CD4+ cell count (>350 cells/mm3) at endline and this association was observed in the short-duration (≤2 years) ART users only. A study among 281 MSM initiating ART and followed for a median of 2 years [18] reported that those with lower nadir CD4+ cell count (<200 cells/mm3) at ART initiation had the highest seroconversion rates, compared to MSM initiating ART at higher CD4+ cell count (≥350 cells/mm3). It is possible that ART-related immune reconstitution during follow-up may have promoted seroconversion, and this was highest among men with the lowest CD4+ cell count, possibly because they had the greatest CD4+ cell count recovery. Although nadir CD4+ cell count was not available in our study, short-duration ART users at endline had a lower baseline CD4+ cell count compared to both the long-duration ART or ART-naive women (median CD4+ count of 324, 461, and 497 cells/mm3, respectively [5]). Although baseline CD4+ cell count was not associated with seroconversion, the subsequent increase in CD4+ cell count at endline through ART-initiated immune reconstitution (median CD4+ cell count among short-duration ART users increased by +103 cells/mm3; IQR: −13 to 196) may have stimulated seroconversion among the recent ART users in response to the high rate of HPV-DNA persistence reported in this cohort [5]. This is also supported by our findings of higher seroconversion rates among women with better ART adherence. An additional explanation for higher seroconversion among short-duration ART users is linked to the higher HPV-DNA prevalence, persistence, and lack of viral clearance in this group compared to prolonged ART users in this cohort [5]. It can be speculated that among recent ART initiators, immune reconstitution may have been not entirely effective to prevent persistence in the short term [5]. Our finding of an association of seroconversion with higher endline (but not baseline) CD4+ count in this study, may reflect the delay required for seroconversion to occur after infection, which might also be influenced by the initial state of immunosuppression. As seen in young HIV-negative women, HPV16 seroconversion occurred between 6 and 12 months after DNA detection [15]. In our study, the duration of HPV-DNA infection at baseline could not be determined. Women taking ART for a prolonged duration (>2 years) had a similar low seroconversion rate as ART-naive women. This may be because women on prolonged ART and strong immune recovery may have fewer prevalent and persistent infections [5], which would be required to trigger seroconversion. The more puzzling finding, however, is that ART-naive women in this study had as high rates of persistent HR-HPV infection as short-duration ART users, and their CD4+ cell count at either time point was not associated with seroconversion. Increases in HPV seropositivity by ART status have been shown to be independent of CD4+ count in other studies among MSM [18] and WLHIV [14]. No study has yet compared seroconversion among ART users and ART-naive women following natural infection, but vaccination studies among WLHIV have shown that, while seroconversion rates are similar among ART users and ART-naive women in the United States and Puerto Rico [21], HPV16 and HPV18 antibody titers were lower among ART-naive but comparable between HIV-negative and ART users [21]. These data suggest there may be some beneficial impact of ART in promoting seroconversion. We found evidence that HPV antibodies detected at baseline provided protection against DNA detection only for HPV18, 35, and 58, for which infection rates were lower. A recent meta-analysis, which assessed whether naturally acquired immunity conferred protection against subsequent infection by the same type [4], reported that HIV-negative women with antibodies against HPV16 and HPV18 had a modest 35% and 30% lower risk of subsequent infection, respectively, against the corresponding type. We found no protection conferred by HPV16 antibodies against HPV16 DNA detection in this study. Others have reported that HPV16 is better able to evade the host immune surveillance relative to other HPV types [22], which may explain its predominance in high-grade cervical lesions in HIV-positive and HIV-negative women [3]. A prospective study among 829 WLHIV risk matched with 413 HIV-negative women in the United States [23] reported no statistically significant difference in the risk of reinfection of any HR-HPV (HPV16/18/31/35/45) among women with same-type seropositivity compared to same-type seronegative at baseline over a median 4.5 years, with the exception of a reduced risk with HPV45. Other studies have evaluated whether HPV antibodies detected at 2 or more time points were associated with subsequent detection of same-type HPV-DNA among HIV-negative women. A prospective study with longitudinal serology measurements among 608 HIV-negative women seen at 6-month intervals for 3 years in the United States [24] reported a reduction in risk of subsequent HPV16 detection among women with a sustained high level of HPV16 antibody (seropositivity at 2 or more time points) and its phylogenetically related types (HPV31/33/58). HPV seropersistence in our study over 16 months was very high; however, there was limited evidence that WLHIV who had type-specific seropersistence had lower HPV-DNA detection compared to women with seroreversion at endline. This finding suggests that seroprevalence, seropersistence, and seroreversion are not good markers of protection against subsequent DNA detection. Given the limited evidence that natural immunity can protect against subsequent infection [4], a multivalent vaccine such as the nonavalent vaccine would be beneficial, given that 55% of WLHIV in this study had multiple HR-HPV infection at baseline, 18% had multiple persistent types at endline [19], and few women were simultaneously infected by all vaccine types. This study was constrained by a limited number of visits between baseline and endline and the overall relatively short follow-up duration. Therefore, we cannot establish whether the seroconversion event occurred in response to either an infection that persisted during follow-up or a baseline infection that cleared followed by new DNA detection of the same type. Moreover, when evaluating the risk of new DNA detection according to same-type seropositivity at baseline, we cannot exclude the possibility that the infection detected at 16 months was a reinfection or a recurrence of a latent undetected infection. However, infrequent condom use, presence of other sexually transmitted infection, or reproductive tract infections (including Chlamydia trachomatis, Trichomonas vaginalis, and bacterial vaginosis), vaginal cleansing, and low CD4+ counts at enrolment were associated with new DNA detection (data not shown). These factors may point to behaviors or factors enhancing the risk of a new sexually acquired infection, or modifiers of vaginal biome or mucosal immunity that may enhance the possibility of reactivation of a latent HPV infection. Analysis of new DNA detection over 16 months according to type-specific positivity was constrained by the small numbers of individual genotype positivity. This study had several important strengths, including its longitudinal design, and the availability of serology and genotyping data at both time points. It is the first study to measure HPV serodynamics longitudinally among WLHIV. In conclusion, this study shows that WLHIV have high HPV seroprevalence and seropersistence of type-specific antibodies. We found evidence of seroconversion over 16 months that was dependent on CD4+ cell count at endline. The high HPV incidence and the limited evidence that naturally acquired antibodies protect against new DNA detection combined with the fact that even though WLHIV have multiple infections, few have been infected with all preventable infections, suggest that WLHIV could benefit from highly multivalent HPV vaccination. Studies, including mathematical modeling studies, assessing the efficacy and cost-effectiveness of nonavalent HPV vaccine, are warranted in this population. Notes Author contributions. Conceived and designed the study: P. M., S. D., H. W., J. D., H. K.; coordinated the study: H. K., A. C., S. D., P. M.; participant recruitment and management: A. C., S. D.; performed the lab testing: H. F., J. N.; analyzed the data: H. K., H. F.; wrote the first draft of the manuscript: H. K.; contributed to the writing of the manuscript: all; criteria for authorship read and met: all; agree with manuscript results and conclusions: all. Acknowledgments.  Contributing members of the HARP study group included: A. Chikandiwa, E. Cutler, S. Delany-Moretlwe, D. A. Lewis, M.P. Magooa, V. Maseko, P. Michelow, B. Muzah, T. Omar, A. Puren (Johannesburg, South Africa); F. Djigma, J. Drabo, O. Goumbri-Lompo, N. Meda, B. Sawadogo, J. Simporé, A. Yonli, S Zan (Ouagadougou, Burkina Faso); V. Costes, M.N. Didelot, S. Doutre, N. Leventoux, N. Nagot, J. Ngou, M. Segondy (Montpellier, France); and A. Devine, C. Gilham, L. Gibson, H. Kelly, R. Legood, P. Mayaud, H.A. Weiss (London, UK). The HARP Study Group also wishes to thank its International Scientific Advisory Group constituting Prof. C. Lacey (Chair, University of York, UK), Prof. Y. Qiao (Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China), Prof. M. Chirenje (University of Harare, Zimbabwe), and Prof. S. de Sanjosé (Institut Catala d’Oncologia, Barcelona, Spain); and the members of the HARP Endpoint Committee including T. Omar (Johannesburg, South Africa), O. Goumbri-Lompo (Ouagadougou, Burkina Faso), S. Doutre, N. Leventoux, V. Costes (Montpellier, France), and O. Clavero (Institut Catala d’Oncologia, Barcelona, Spain). Financial support. This work was supported by the European Commission 7th Framework Programme (grant number HEALTH-2010-F2-265396); and the UK Medical Research Council PHINDS scheme (grant number PH01/14-39). Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. Presented in part: 31th International Papillomavirus Conference, Cape Town, South Africa, abstract number 404, 28 February to 4 March 2017. References 1. de Sanjose S , Quint WG , Alemany L , et al. ; Retrospective International Survey and HPV Time Trends Study Group . 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The Journal of Infectious DiseasesOxford University Press

Published: May 30, 2018

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