Perinatally acquired HIV-infected female youth (PHIV) had an almost 2 times higher chance of having anogenital high-risk human papillomavirus (HR-HPV) incidence and persistence than Human Immunodeficiency Virus-uninfected youth. As HR-HPV persistence strongly predicts cancer development, PHIV should be urgently prioritized for HPV vaccination.
Keywords: HIV, human papillomavirus, adolescent, perinatal, persistence
Abstract
Background
Female youth with perinatally acquired human immunodeficiency virus (PHIV) may be at higher risk than uninfected youth for persistent anogenital human papillomavirus (HPV) infection, due to prolonged immunodeficiency.
Methods
A 3-year cohort study was conducted between 2013 and 2017 among Thai and Vietnamese PHIV and HIV-uninfected females 12–24 years, matched by age group and number of lifetime sexual partners. For HPV genotyping, cervical and anal samples were obtained at baseline and annually. Vaginal samples were collected at baseline and every 6 months. Factors associated with high-risk HPV (HR-HPV) persistence and incidence were assessed.
Results
We enrolled 93 PHIV and 99 HIV-uninfected females. Median age was 19 (interquartile range [IQR] 18–20) years. For the 7 HR-HPV types (16, 18, 31, 33, 45, 52, 58) in the nonavalent HPV vaccine, PHIV had significantly higher incidence (P = .03) and persistence (P = .01) than HIV-uninfected youth over a 3-year period. Having HIV (adjusted hazard ratio [aHR] 2.1, 95% confidence interval [CI] 1.1–3.9) and ever using illegal substances (aHR 4.8, 95% CI 1.8–13.0) were associated with incident 7 HR-HPV infections. HIV-positive status (adjusted prevalence ratio [aPR] 2.2, 95% CI 1.5–3.2), recent alcohol use (aPR 1.75, 95% CI 1.2–2.5), and higher number of lifetime partners (aPR 2.0, 95% CI 1.4–3.1, for 3–5 partners; aPR 1.93, 95% CI 1.2–3.2, for ≥6 partners) were significantly associated with persistent 7 HR-HPV infections.
Conclusions
Female PHIV were at higher risk of having anogenital HR-HPV acquisition and persistence. Primary and secondary prevention programs for HPV infection and HPV-related diseases should be prioritized for PHIV children and youth.
A growing number of female adolescents and young adults living with perinatally acquired HIV (PHIV) are sexually active and at risk of sexually transmitted infections (STI) [1]. Human papillomavirus (HPV) is one of the most common STIs. High-risk HPV (HR-HPV) types are associated with anogenital cancers, and persistent HR-HPV infection is known as the strongest predictor for cancer development [2, 3]. Among women living with human immunodeficiency virus (HIV), use of antiretroviral therapy (ART) has been demonstrated to reduce cervical HR-HPV infection and cervical precancerous and cancerous lesions, although the benefit may be limited to countries with high ART coverage and treatment initiation prior to substantial immune system decline [4]. In addition, HPV prevalence at all sites remains higher in individuals with HIV compared to those who are uninfected, regardless of ART or known risk factors.
PHIV youth have frequently experienced prolonged immunosuppression prior to ART, due in large part to delays in diagnosis and treatment initiation [5–7]. The potential for poorer immune function when first exposed to HR-HPV could put PHIV youth at greater risk for HR-HPV acquisition and persistence than adolescents and young women who acquire HIV later in life. Moreover, most youth living with HIV are in low- and middle-income countries where access to HPV vaccination programs are limited and frequently restricted to younger female children [8]. Weak health infrastructure to provide primary and secondary prevention of HPV-related diseases and other STIs adds to the burden of short-term and long-term sexual health problems in these contexts. In light of the limited available prevention resources, identifying subgroups of female adolescents at greater risk of HR-HPV infection could help to prioritize catch-up vaccination programs. We conducted an observational cohort study to assess the impact of perinatal HIV infection and other behavioral factors on the persistence and acquisition of anogenital HR-HPV infection among Asian female youth.
METHODS
We conducted a longitudinal observational cohort study (the HPV in Adolescents Study) to compare the prevalence, incidence, and persistence of anogenital and oral HPV infections in PHIV and HIV-uninfected female and male adolescents in Thailand and Vietnam. Study data are presented for anogenital HPV infection in female youth.
Study participants. We recruited females aged 12–24 years who reported a history of vaginal sex from 5 study sites in Thailand—Thai Red Cross AIDS Research Centre (TRCARC) and Siriraj Hospital Mahidol University in Bangkok, and Chiangrai Prachanukroh Hospital in Chiang Rai; and Vietnam—Children’s Hospital 1 and Hung Vuong Hospital in Ho Chi Minh City. PHIV were matched to HIV-uninfected females by age group (12–15, 16–18, 19–21, 22–24 years) and number of lifetime sex partners (≤ or >3). Being pregnant at the screening visit, having an untreated symptomatic STI (except genital warts), history of HPV vaccination, and inability to independently complete the study’s audio computer-assisted self-interview (ACASI) were exclusion criteria. Individuals were further excluded if they had compromised immune function due to other chronic diseases or used immunosuppressive medications.
Ethics Reviews
The institutional review boards at the coordinating center (amfAR/TREAT Asia) and at each participating study site approved the study protocol and informed consent/assent documents. Consent procedures were conducted in local languages (Thai or Vietnamese) by trained study staff. Participants <18 years of age were asked for their assent, whereas their parents/guardians provided consent; they were subsequently consented after the age of 18. Those 18 and older provided their own consent at study entry.
Study Procedures
At their baseline/enrollment study visit, female participants completed a questionnaire to assess behavioral and sexual risks and had blood samples obtained for testing, including syphilis serology, and CD4 count and plasma HIV RNA (for PHIV) or HIV antibody (if HIV-uninfected). Urine samples were collected for pregnancy tests. Physicians performed anogenital examinations and collected cervical, vaginal, and anal swabs that were placed in separate containers of liquid-based cytology fluid (ThinPrep® PAP test, Hologic®, Inc., Marlborough, MA, USA) for testing: cervix—cytology, HPV genotyping, E6/E7 mRNA, E6 oncoproteins, Chlamydia, and gonorrhea testing, and herpes simplex virus type 2 (HSV-2) testing; vagina—HPV genotyping; anus—HPV genotyping. Anogenital examination and vaginal swab collection were conducted every 6 months thereafter, whereas other procedures were repeated annually. All blood tests were performed at study site laboratories. Liquid-based cytology fluid samples were stored at −20 to −70°C prior to shipment to the study’s central laboratory at TRCARC.
HPV and Other STI Testing
Chlamydia and gonorrhea testing (Abbott RealTime CT/NG Assay, Abbott Molecular Inc., Des Plaines, IL, USA; Cobas4800 CT/NG Test, Roche Molecular Systems, Inc., Branchburg, NJ, USA), HSV-2 (HSV I & II Typing Real Time PCR Kit, Shanghai ZJ Bio-Tech Co. Ltd., Shanghai, China), and HPV-related testing were conducted on cervical liquid-based cytology fluid at the central laboratory.
HPV genotyping was conducted using the LINEAR ARRAY test (LA HPV GT, Roche Molecular Systems, Inc.) to identify 37 HPV DNA genotypes including the 13 HR-HPV genotypes: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Cervical liquid-based cytology fluid samples were also used to detect E6/E7 mRNA by flow cytometric analysis (HPV OncoTect™ E6, E7 mRNA test, incellDx, Carlos, CA, USA) and E6 oncoproteins (AV Avantage HPV E6 Test, Arbor Vita Corp., Fremont, CA, USA).
Cytology and Histology
Cervical cytology results were classified using the 2001 Bethesda system as normal, atypical squamous cell of undetermined significance (ASC-US), atypical squamous cells—these cannot exclude high-grade squamous intraepithelial lesion (ASC-H), low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), or carcinoma [9]. Histology results were categorized as atypia, cervical intraepithelial neoplasia (CIN) 1, CIN 2, CIN 3, carcinoma in situ, and invasive carcinoma. Those with ASC-H, LSIL, HSIL, and atypical glandular cells or carcinoma on cervical cytology were referred for colposcopy, with biopsies taken of abnormal tissue or endocervical curettage after inspection. Those with ASC-US on cervical cytology and concomitant detection of HR-HPV type or E6/E7 mRNA or E6 oncoproteins also were referred for colposcopy. Treatment according to final histologic diagnoses were at the discretion of the local gynecologist.
Statistical Methods
Incidence of any anogenital HR-HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68), of the 7 HR-HPV types in the nonavalent HPV vaccine (7 HR-HPV; 16, 18, 31, 35, 45, 52, 58), or of the HPV types 16 and/or 18 (HPV 16/18) was defined as a new acquisition of at least 1 HR-HPV type in any of the cervical, vaginal, or anal compartments (as detected by the Linear Array) during the follow-up period. Persistence of any HR-HPV types, 7 HR-HPV types, or HPV 16/18 was defined as having a specific HR-HPV type for ≥48 weeks or at ≥2 consecutive visits in any of the anogenital compartments during the follow-up period. If HPV vaccination occurred during the study period, data were censored from the point of vaccination onward. A χ 2 or Wilcoxon test was used to assess differences by HIV status. The Kaplan-Meier method was used to estimate the persistence probability and cumulative incidence of HR-HPV infections.
Generalized estimating equations methods with a log link and an exchangeable correlation matrix (Poisson GEE) were used to assess factors associated with the persistence or acquisition of any anogenital HR-HPV types, with further subgroup analyses of the 7 HR-HPV types and of HPV 16/18 alone. Covariates with P-value < .10 in univariate analysis were adjusted for in multivariate models. Statistical significance in the final multivariate model was identified using a 2-sided P-value of .05. Data management and statistical analyses were performed using SAS 9.4 for Windows (SAS Institute Inc., Cary, NC, USA) and Stata (Stata Corp, STATA 14 for Windows, College Station, TX, USA).
RESULTS
Participant Characteristics
From June 2013 to July 2015, we enrolled 93 PHIV and 99 HIV-uninfected female youth; overall median age was 19 (interquartile range [IQR], 18–20) years, and 39% had ever been pregnant. For PHIV youth, 94% were on ART with a median duration of 4.1 (IQR 2.5–6.5) years. Median baseline CD4 count was 593 (IQR 392–808) cells/mm3 and 62% were virally suppressed (HIV RNA < 40 copies/mL). PHIV youth reported being less likely to ever drink alcohol (77% vs 91%, P = .01), smoke cigarettes (29% vs 45%, P = .02), and use illegal substances (8% vs 19%, P = .02) (Table 1). Consistent condom use for vaginal sex in the past 6 months was reported more frequently (33% vs 11%, P = .001) among PHIV than HIV-uninfected youth. The median number of lifetime sex partners of 2 (IQR 1–3) and in the past 6 months of 1 (IQR 1–1) were similar between the 2 groups.
Table 1.
Characteristics at Study Enrollment of Female Youth With and Without Perinatally Acquired Human Immunodefiency Virus Infection
| Characteristic | With Perinatally Acquired HIV (n = 93) | HIV-Uninfected (n = 99) | Total (n = 192) | P value |
|---|---|---|---|---|
| Study site | ||||
| Thailand, no. (%) | 86 (92) | 91 (92) | 177 (92) | .87 |
| Vietnam, no. (%) | 7 (8) | 8 (8) | 15 (8) | |
| Median (IQR) age, years | 19 (18–20) | 19 (17–20) | 19 (18–20) | .27 |
| Age group, no. (%), years | ||||
| <18 | 31 (33) | 19 (19) | 50 (26) | .06 |
| 18 to <20 | 36 (39) | 52 (53) | 88 (46) | |
| ≥20 | 26 (28) | 28 (28) | 54 (28) | |
| Median (IQR) BMI, kg/m 2 | 19 (17–21) | 20 (18–23) | 20 (18–22) | .004 |
| BMI, no. (%) | ||||
| <18 kg/m2 | 31 (33) | 17 (17) | 48 (25) | .01 |
| ≥18 kg/m2 | 62 (67) | 82 (83) | 144 (75) | |
| Pregnancy history, no. (%) | ||||
| Never been pregnant | 62 (67) | 55 (56) | 117 (61) | .12 |
| Ever been pregnant | 31 (33) | 44 (44) | 75 (39) | |
| Education, no. (%) | ||||
| Primary school or secondary school | 32 (34) | 22 (22) | 54 (28) | .001 |
| Vocational school/pre- University | 5 (5) | 23 (23) | 28 (15) | |
| University | 8 (9) | 18 (18) | 26 (14) | |
| Nonformal education | 5 (5) | 5 (5) | 10 (5) | |
| Lower than primary school | 43 (46) | 31 (32) | 74 (38) | |
| Alcohol use, no. (%) | ||||
| Ever | 72 (77) | 89 (91) | 161 (84) | .01 |
| Past 6 months | 43 (46) | 59 (60) | 102 (53) | .06 |
| Cigarette smoking, no. (%) | ||||
| Ever | 27 (29) | 44 (45) | 71 (37) | .02 |
| Past 6 months | 21 (23) | 29 (29) | 50 (26) | .29 |
| Illegal substance use, no. (%) | ||||
| Ever | 7 (8) | 19 (19) | 26 (14) | .02 |
| Amphetamine-type stimulants | 5 (5) | 13 (13) | 18 (9) | .09 |
| Past 3 months | 4 (4) | 4 (4) | 8 (4) | .02 |
| Median (IQR) number of lifetime sex partner | 2 (1–3) | 2 (1–3) | 2 (1–3) | .76 |
| Lifetime sex partners, no. (%) | ||||
| 1 | 34 (37) | 37 (37) | 71 (37) | .73 |
| 2 | 20 (21) | 21 (21) | 41 (21) | |
| 3–5 | 26 (28) | 32 (32) | 58 (31) | |
| ≥6 | 13 (14) | 9 (9) | 22 (11) | |
| Median (IQR) number of sex partners, past 6 months | 1 (1) | 1 (1) | 1 (1) | .74 |
| Sex partners, past 6 months, no. (%) | ||||
| 1 | 86 (92) | 92 (93) | 178 (93) | .15 |
| 2 | 7 (8) | 4 (4) | 11 (6) | |
| 3–5 | 0 (0) | 3 (3) | 3 (2) | |
| ≥6 | 0 | 0 | 0 | |
| Condom use with vaginal sex, past 6 months, no. (%) | ||||
| Always | 31 (33) | 11 (11) | 42 (22) | .001 |
| Sometimes/Never | 60 (65) | 85 (86) | 145 (76) | |
| Not Applicable/Not having sex this route | 2 (2) | 3 (3) | 5 (2) | |
| Condom use with anal sex, past 6 months, no. (%) | ||||
| Always | 0 (0) | 0 (0) | 0 (0) | .15 |
| Sometimes/Never | 4 (4) | 1 (1) | 5 (3) | |
| Not Applicable/Not having sex this route | 88 (96) | 98 (99) | 186 (97) | |
| History of STIs, no. (%) | ||||
| Yes | 24 (26) | 16 (16) | 40 (21) | .10 |
| No | 69 (74) | 83 (84) | 152 (79) | |
| Baseline STIs, laboratory-diagnosed, no. (%) | 26 (28) | 25 (25) | 51 (27) | .67 |
| Syphilis | 2 (2) | 2 (2) | 4 (2) | .99 |
| Chlamydia | 24 (26) | 20 (20) | 44 (23) | .39 |
| Gonorrhea | 5 (5) | 0 (0) | 5 (3) | .03 |
| Herpes simplex virus type 2 | 0 (0) | 3 (3) | 3 (2) | .25 |
| HIV-related clinical characteristics | ||||
| Currently on ART, no. (%) | 87 (94) | |||
| Median (IQR) duration on ART, years | 4.1 (2.5–6.5) | |||
| Undetectable viral load (HIV RNA <40 copies/mL), no. (%) | 58 (62) | |||
| Median (IQR) CD4 count, cells/mm3 | 593 (392–808) |
Abbreviations: ART, antiretroviral therapy; BMI, body mass index; HIV, human immunodeficiency virus; IQR, interquartile range; HPV 16/18, human papillomavirus types 16 and/or 18; HR-HPV, high-risk human papillomavirus; STI, sexually transmitted infections.
Participants were followed for a median of 3.01 (IQR 2.93–3.10) years contributing to 277 person-years in PHIV and 270 person-years in HIV-uninfected youth. Three PHIV participants died. Twenty-nine (10 PHIV and 19 HIV-uninfected) participants were lost to follow-up.
Baseline Asymptomatic STIs and Anogenital HR-HPV Infection
Syphilis was found in 2% of both PHIV and HIV-uninfected youth. Chlamydia was diagnosed in 26% of PHIV and 20% of HIV-uninfected youth (P = .39). Gonorrhea was more common in PHIV than HIV-uninfected youth (5% vs 0%, P = .03). No PHIV and 3% of HIV-uninfected youth had HSV-2 infection (Table 1).
Anogenital HR-HPV of any type was more common among PHIV than HIV-uninfected youth (86% vs 73%, P = .02) throughout the study period. For 7 HR-HPV, 74% of PHIV and 58% of HIV-uninfected youth had these subtypes detected (P = .02). HPV 16/18 was found in 48% of PHIV and 42% of HIV-uninfected youth (P = .41, data not shown).
Anogenital HR-HPV Incidence and Persistence ( Figure 1 and Figure 2)
Figure 1.
Probability of incident anogenital high-risk human papillomavirus infection in female youth with and without perinatally acquired HIV infection. A, Any HR-HPV types. B, 7 HR-HPV types in the nonavalent vaccine. C, HPV 16 and/or HPV 18. Abbreviations: HPV 16/18, human papillomavirus types 16 and/or 18; HR-HPV, high-risk human papillomavirus; PHIV, perinatally acquired human immunodeficiency virus infection.
Figure 2.
Proportion of persistence of anogenital HR-HPV infection in female youth with and without perinatally acquired HIV. A, Any HR-HPV types. B, 7 HR-HPV types in the nonavalent vaccine. C, HPV 16 and/or HPV 18. Four participants dropped out at baseline: youth without HIV were lost to follow-up and 2 youth (1 HIV-uninfected and 1 PHIV) were censored at vaccination. Abbreviations: HIV, human immunodeficiency virus; HPV 16/18, human papillomavirus types 16 and/or 18; HR-HPV, high-risk human papillomavirus; PHIV, perinatally acquired HIV infection.
PHIV and HIV-uninfected youth had similar incidence of any HR-HPV (41% vs 44% at week 48, 80% vs 60% at week 144, P = .15). PHIV, however, had higher incidence of 7 HR-HPV than HIV-uninfected youth (28% vs 17% at week 48, 64% vs 40% at week 144, P = .03).
Persistence of any HR-HPV (56% vs 31% at week 48, 21% vs 5% at week 144, P = .01) and 7 HR-HPV (65% vs 42% at week 48, 27% vs 10% at week 144, P = .01) were found in higher proportions of PHIV than HIV-uninfected youth.
Cervical Cytology, HPV-related Biomarkers, and Cervical Histology
At baseline, PHIV had higher rates of abnormal cervical cytology results (from ASC-US and above) compared to HIV-uninfected youth (33% vs 16%, P = .01) with similar degrees of difference seen throughout the study (Supplemental Table 1). E6/E7 mRNA was detected in 44% (baseline), 59% (month 12), 55% (month 24), and 65% (month 36) of cervical samples; differences by HIV status were observed at the baseline time point (35% in PHIV vs 52% in HIV-uninfected, P = .03, data not shown). E6 and E7 oncoproteins for either HPV 16 or 18 were positive in 0–2% of participants throughout the study.
Of 20 participants who met colposcopy referral criteria at enrollment and had colposcopic examination, 8 (40%) had biopsies done after visual inspection: 3 had CIN 1 and 1 had CIN 3, all were PHIV youth (data not shown). Over the study period, 6 (5 PHIV and 1 HIV-uninfected) developed CIN 1, 2 (2 PHIV) had CIN 2 and 1 (1 PHIV) had CIN 3.
Factors Associated With Incidence of Anogenital HR-HPV Infection
The risk of having incident 7 HR-HPV infection significantly increased with having perinatally acquired HIV (adjusted hazard ratio [aHR] 2.1, 95% CI 1.1–3.9) and ever using illegal substances (aHR 4.8, 95% CI 1.8–13.0) (Supplemental Table 2). None of the HIV-related factors assessed were found to be associated with HR-HPV incidence among PHIV youth (Supplemental Table 3).
Factors Associated With Persistence of Anogenital HR-HPV Infection
The risk of having persistent infection with 7 HR-HPV types, by Poisson GEE analysis, significantly increased with having perinatally acquired HIV infection (adjusted prevalence ratio [aPR], 2.2, 95% CI 1.5–3.2), alcohol use in the past 6 months (aPR 1.8, 95% CI 1.2–2.5), and higher numbers of lifetime sex partners (aPR 2.0, 95% CI 1.4–3.1, for 3–5 partners and aPR 1.9, 95% CI 1.2–3.2, for ≥6 partners) (Table 2). Similar associations were seen for the persistence of any HR-HPV types. We did not identify HIV-specific factors related to persistence of anogenital HR-HPV infection (eg, current CD4 count, HIV RNA, World Health Organization clinical staging) in models run for PHIV youth (Table 3).
Table 2.
Factors Associated With Persistence of Anogenital High-risk Human Papillomavirus Infection
| Covariate | Any HR-HPV | 7 HR-HPV in the Nonavalent Vaccine | HPV 16/18 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | Univariate | Multivariate | |||||||
| PR (95% CI) | P value | aPR (95% CI) | P value | PR (95% CI) | P value | aPR (95% CI) | P value | PR (95% CI) | P value | aPR (95% CI) | P value | |
| HIV status | .001 | .001 | .001 | <.001 | .09 | .09 | ||||||
| HIV-uninfected | Ref | Ref | Ref | \Ref | Ref | Ref | ||||||
| Perinatally HIV-infected | 1.8 (1.3–2.6) | 1.8 (1.3–2.6) | 2.1 (1.35–3.2) | 2.2 (1.5–3.2) | 1.7 (.9–3.3) | 1.6 (.9–3.0) | ||||||
| Education | .28 | .35 | .93 | |||||||||
| Primary school or secondary school | 0.9 (.6–1.3) | 1.0 (.99–1.0) | 1.0 (.9–1.2) | |||||||||
| Vocational school/pre-University | 0.5 (.2–1.0) | 1.0 (.9–1.0) | 1.0 (.8–1.2) | |||||||||
| University | 0.8 (.5–1.3) | 0.9 (.9–1.0) | 1.0 (.7–1.3) | |||||||||
| Non-formal education | 0.6 (.3–1.6) | 1.0 (.9–1.0) | 0.9 (.7–1.2) | |||||||||
| Lower than primary school | Ref | Ref | Ref | |||||||||
| Pregnancy history | .80 | .35 | .73 | |||||||||
| Never been pregnant | 1.0 (.8–1.3) | 1.1 (.9–1.2) | 1.0 (.9–1.1) | |||||||||
| Ever been pregnant | Ref | Ref | Ref | |||||||||
| Current age (years) | .10 | .15 | .08 | .07 | .11 | |||||||
| <18 | 1.1 (1.0–1.2) | 1.0 (.99–1.0) | 1.1 (1.0–1.3) | 1.1 (1.0–1.3) | 1.1 (1.0–1.1) | |||||||
| ≥18 | Ref | Ref | Ref | Ref | Ref | |||||||
| BMI (kg/m 2) | .01 | .08 | .19 | .13 | ||||||||
| <18 | 1.5 (1.1–2.1) | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.2 (1.0–1.5) | ||||||||
| ≥18 | Ref | Ref | Ref | Ref | ||||||||
| Alcohol use, ever | .27 | .07 | .18 | .49 | ||||||||
| Yes | 1.4 (.8–2.4) | 1.0 (1.0–1.0) | 1.4 (.8–2.6) | 1.1 (.8–1.5) | ||||||||
| No | Ref | Ref | Ref | Ref | ||||||||
| Alcohol use, past 6 months | .01 | .001 | .01 | .003 | .19 | |||||||
| Yes | 1.7 (1.2–2.4) | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.8 (1.2–2.5) | 1.1 (1.0–1.2) | |||||||
| No | Ref | Ref | Ref | Ref | Ref | |||||||
| Cigarette smoking, ever | .58 | .18 | .17 | |||||||||
| Yes | 1.1 (.8–1.4) | 1.0 (.99–1.0) | 1.2 (.9–1.5) | |||||||||
| No | Ref | Ref | Ref | |||||||||
| Cigarette smoking, past 6 months | .24 | .65 | .16 | |||||||||
| Yes | 1.2 (.9–1.8) | 1.0 (.99–1.0) | 1.2 (.9–1.6) | |||||||||
| No | Ref | Ref | Ref | |||||||||
| Substance use, ever | <.001 | .40 | .35 | .17 | ||||||||
| Yes | 2.4 (1.5–3.7) | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.3 (.9–2.0) | ||||||||
| No | Ref | Ref | Ref | Ref | ||||||||
| Number of sex partners, past 6 months | .09 | .65 | .12 | .004 | .81 | |||||||
| <2 | Ref | Ref | Ref | Ref | Ref | |||||||
| ≥2 | 1.0 (1.0–1.0) | 1.0 (.99–1.0) | 1.0 (1.0–1.0) | 1.2 (1.1–1.4) | 1.0 (.99–1.0) | |||||||
| Lifetime number of sex partners | <.001 | .001 | .001 | .001 | .001 | <.001 | ||||||
| <3 | Ref | Ref | Ref | Ref | Ref | Ref | ||||||
| 3–5 | 2.0 (1.4–3.0) | 2.1 (1.5–3.0) | 2.2 (1.4–3.3) | 2.0 (1.4–3.1) | 2.4 (1.2–5.1) | 2.5 (1.2–5.1) | ||||||
| ≥6 | 2.1 (1.3–3.3) | 1.9 (1.3–3.0) | 2.4 (1.5–4.1) | 1.9 (1.2–3.2) | 4.2 (1.9–8.8) | 3.9 (1.9–8.3) | ||||||
| Frequency of sexual act per week, past 6 months | .03 | .17 | .26 | .19 | ||||||||
| <4 | Ref | Ref | Ref | Ref | ||||||||
| ≥4 | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | ||||||||
| Condom use with vaginal sex, past 6 months | .73 | .80 | .18 | |||||||||
| Always | Ref | Ref | Ref | |||||||||
| Sometimes/Never | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | |||||||||
| Not applicable/Not having sex this route | 1.0 (1.0–1.0) | 1.0 (1.0–1.0) | 1.0 (.9–1.0) | |||||||||
| History of STIs | .08 | .581 | .034 | .54 | .33 | |||||||
| Yes | 1.5 (1.0–2.5) | 1.0 (1.0–1.0) | 1.01 (1.0–1.0) | 1.2 (.8–1.7) | 1.2 (.8–1.7) | |||||||
| No | Ref | Ref | Ref | Ref | Ref |
Abbreviations: aPR, adjusted prevalence ratio; BMI, body mass index; CI, confidence interval; HIV, human immunodeficiency virus; HR-HPV, high-risk human papillomavirus; HPV 16/18, human papillomavirus types 16 and/or 18; PR, prevalence ratio; Ref, reference; STI, sexually transmitted infection.
Table 3.
Factor Associated With Persistence of Anogenital High-risk Human Papillomavirus Infection Among Female Youth With Perinatally Acquired Human Immunodefiency Virus Infection
| Covariate | Any HR-HPV | 7 HR-HPV in the Nonavalent Vaccine | HPV 16/18 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Univariate | Multivariate | Univariate | Multivariate | Univariate | Multivariate | |||||||
| PR (95% CI) | P value | aPR (95% CI) | P value | PR (95% CI) | P value | aPR (95% CI) | P value | PR (95% CI) | P value | aPR (95% CI) | P value | |
| Current CD4, cells/mm 3 | .39 | .98 | .89 | |||||||||
| <350 | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.8–1.2) | |||||||||
| ≥ 350 | Ref | Ref | Ref | |||||||||
| Current HIV RNA, copies/mL | .80 | .03 | .09 | |||||||||
| ≤40 | Ref | Ref | Ref | Ref | ||||||||
| >40 | 1.0 (.99–1.0) | 1.6 (1.1–2.4) | 1.0 (.99–1.0) | 1.0 (.9–1.2) | .71 | |||||||
| Current WHO stage | .24 | .42 | .85 | |||||||||
| Stage 1 or 2 | 1.0 (.99–1.0) | 1.4 (.3–7.0) | 1.0 (.8–1.3) | |||||||||
| Stage 3 | 1.0 (.99–1.0) | 1.6 (.3–8.1) | 0.8 (.6–1.0) | |||||||||
| Stage 4 | Ref | Ref | Ref | |||||||||
| Education | .73 | .01 | .72 | .97 | ||||||||
| Primary school or secondary school | 1.0 (.99–1.0) | 1.0 (.9–1.0) | 1.0 (.99–1.0) | 1.0 (.9–1.2) | ||||||||
| Vocational school/pre-University | 1.0 (.99–1.0) | 1.1 (1.0–1.2) | 1.0 (1.0–1.1) | 1.0 (.9–1.2) | ||||||||
| University | 1.0 (.99–1.0) | 1.1 (.9–1.4) | 1.0 (1.0–1.0) | 1.0 (.7–1.4) | ||||||||
| Non-formal education | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.9–1.0) | 1.0 (.8–1.2) | ||||||||
| Lower than primary school | Ref | Ref | Ref | Ref | ||||||||
| Pregnancy history | .47 | .32 | .61 | |||||||||
| Never been pregnant | 1.2 (.8–1.8) | 1.3 (.8–2.2) | 1.2 (.5–2.9) | |||||||||
| Ever been pregnant | Ref | \Ref | Ref | |||||||||
| Current age (years) | .28 | .99 | .42 | |||||||||
| <18 | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.05 (.9–1.2) | |||||||||
| ≥18 | Ref | Ref | Ref | |||||||||
| BMI (kg/m 2) | .16 | .77 | .21 | |||||||||
| <18 | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.1 (.9–1.4) | |||||||||
| ≥18 | Ref | Ref | Ref | |||||||||
| Alcohol use, ever | .10 | .27 | .001 | .001 | .43 | |||||||
| Yes | 1.0 (.99–1.0) | 1.0 (.9–1.1) | 1.0 (.99–1.0) | 1.1 (1.0–1.2) | 1.1 (.9–1.4) | |||||||
| No | Ref | Ref | Ref | Ref | Ref | |||||||
| Alcohol use, past 6 months | .01 | .02 | .001 | .19 | .14 | |||||||
| Yes | 1.0 (.99–1.0) | 1.0 (1.0–1.0) | 1.1 (1.0–1.1) | 1.0 (.99–1.0) | 1.1 (1.0–1.2) | |||||||
| No | Ref | Ref | Ref | Ref | Ref | |||||||
| Cigarette smoking, ever | .69 | .49 | .58 | |||||||||
| Yes | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.1 (.8–1.5) | |||||||||
| No | Ref | Ref | Ref | |||||||||
| Cigarette smoking, past 6 months | .72 | .46 | .99 | |||||||||
| Yes | 1.0 (.99–1.0) | 0.8 (.4–1.4) | 1.0 (.7–1.5) | |||||||||
| No | Ref | Ref | Ref | |||||||||
| Substance use, ever | .32 | .77 | .34 | |||||||||
| Yes | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.3 (.7–2.4) | |||||||||
| No | Ref | Ref | Ref | |||||||||
| Number of sex partners, past 6 months | .18 | .62 | .15 | |||||||||
| <2 | Ref | Ref | Ref | |||||||||
| ≥2 | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.99–1.1) | |||||||||
| Lifetime number of sex partners | .004 | .001 | .0 | .002 | .004 | .001 | ||||||
| <3 | Ref | Ref | Ref | Ref | Ref | Ref | ||||||
| 3–5 | 1.9 (1.2–2.8) | 1.9 (1.2–2.8) | 1.8 (1.1–3.0) | 1.8 (1.1–3.0) | 2.1 (.8–5.4) | 2.0 (.8–5.3) | ||||||
| ≥6 | 2.0 (1.3–3.1) | 2.0 (1.3–3.1) | 2.1 (1.2–3.5) | 2.1 (1.2–3.5) | 4.2 (1.8–9.9) | 4.0 (1.7–9.5) | ||||||
| Frequency of sexual act per week, past 6 months | .73 | .01 | .48 | .26 | ||||||||
| <4 | Ref | Ref | Ref | Ref | ||||||||
| ≥4 | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.99–1.1) | ||||||||
| Condom use with vaginal sex, past 6 months | .29 | .10 | .38 | |||||||||
| Always | Ref | Ref | Ref | |||||||||
| Sometimes/Never | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.99–1.0) | |||||||||
| Not applicable/Not having sex this route | 1.0 (.99–1.0) | 1.0 (.99–1.0) | 1.0 (.97–1.0) | |||||||||
| History of STIs | .18 | .12 | .065 | .19 | ||||||||
| Yes | 1.0 (.99–1.0) | 1.4 (.9–2.2) | 1.1 (.99–1.3) | 1.1 (.9–1.4) | ||||||||
| No | Ref | Ref | Ref |
Abbreviations: aHR, adjusted prevalence ratio; BMI, body mass index; CI, confidence interval; HIV, human immunodeficiency virus; HPV 16/18, human papillomavirus types 16 and/or 18; HR-HPV, high-risk human papillomavirus; PR, prevalence ratio; Ref, reference; STI, sexually transmitted infection; WHO, World Health Organization.
DISCUSSION
An estimated 150 000 adolescents aged 10–19 years were living with HIV in the Asia-Pacific in 2017 [10]. Increasing proportions of female youth in the region with perinatally acquired HIV infection are becoming sexually active [11–13]. Among sexually active PHIV female youth in our study in Thailand and Vietnam, we found 65% who inconsistently used condoms and almost 10% with multiple partners in the past 6 months, putting them at risk for STIs including HPV. Although with lower risk behaviors reported as compared to youth without HIV, PHIV youth demonstrated significantly higher prevalence, higher persistence, and higher incidence of anogenital HR-HPV infections over the 3-year follow-up period. Having perinatally acquired HIV roughly doubled the chance of HR-HPV persistence and incidence.
Successful ART has tended to have a beneficial effect on the natural history of anogenital HPV infection and its related diseases in adult and youth living with HIV [14–16]. However, prolonged immunosuppression and subsequent inability to fully restore immune function after ART are proposed explanations for the limited benefit of ART on the reduction of cervical HR-HPV infection and HPV-related precancerous and cancerous lesions among women living with HIV in countries where inadequate coverage and delayed initiation of ART are common [4]. PHIV female youth are even more likely to have been living longer in an immunocompromised state and having suboptimal immune function when exposed to or after acquiring HR-HPV infection compared to those who acquire HIV as adults. HR-HPV could therefore have a higher chance and longer time to persist in PHIV, regardless of post-ART immune recovery.
Because persistent anogenital HR-HPV infections are the strongest predictor for the development of cervical and anal cancers [2, 3] the significantly higher rates of anogenital HR-HPV persistence in PHIV female youth than HIV-uninfected youth demonstrated in our study point to the need for urgent establishment of primary and secondary HPV prevention programs for PHIV in this region. The 56% persistence of any anogenital HR-HPV type at 1 year among the PHIV in our study is close to the 58% reported among adult women with HIV in Brazil [10]. However, the persistence of any HR-HPV of 21% among PHIV youth at 3 years in our study is lower than the 50% observed among US youth with sexually acquired HIV infection in the early ART era [17]. Although this may be due to the high proportion of youth not taking ART (54%) in the US cohort at that time, we did not identify HIV-related factors (including current CD4 count, HIV RNA suppression, duration on ART) to be associated with persistence of HR-HPV.
PHIV youth in our study had an incidence of any HR-HPV infection of 41% at 1 year, which is much higher than 11% reported among Brazilian women with HIV [18]. In addition to having perinatally acquired HIV, ever using illegal substances was associated with the acquisition of the 7 HR-HPV types in the nonavalent vaccine among youth in our study. Fourteen percent of our youth reported ever using illegal substances, and amphetamine-type stimulants were the most common substances used. Laboratory and animal models have suggested that methamphetamine could alter innate and adaptive immunity among users through modifications of cellular components and functions leading to immunosuppression [19]. Although younger women are more likely to acquire initial and multiple HPV genotype infections due in part to cervical ectopy [17, 20] the high incidence of HR-HPV we observed among PHIV youth points to the importance of implementing catch-up HPV vaccination programs in our region, which should be prioritized for those living with HIV during childhood and early adolescence.
Recent modeling data demonstrated that cervical cancer could be eliminated in the next 2 decades in Australia if the country maintains high coverage of nonavalent HPV vaccination among girls and boys (including catch-up vaccination programs) and of adult HPV testing every 5 years [21]. However, most Asian and African countries with the highest numbers of PHIV female youth still lack national policies to support HPV vaccination or have programs that rarely allow for catch-up vaccination for those who have aged beyond the national program [8]. For example, Thailand only allows access to HPV vaccine for girls 10–12 years of age without a catch-up program [22]. Although proved to be cost-effective, many low- and middle-income countries still cannot include HPV vaccine in their national immunization programs due to the high costs of procuring the bivalent, quadrivalent, and nonavalent HPV vaccines from originator companies. More efficient and concerted efforts, especially among countries that are not eligible to access subsidized vaccine costs through Gavi, the Vaccine Alliance, are needed to bring these prices down.
Our study limitations include not having data on nadir CD4 count to evaluate associations with the level of immunosuppression prior to ART. In addition, following consultations with researchers, providers, and communities involved in the study during protocol development, we only collected vaginal swab samples at the midyear visit rather than speculum and anal examinations in order to reduce the frequency of invasive study procedures. Although this limited the HPV sampling data, multiple studies have shown a high degree of concordance between HR-HPV types across anogenital compartments in women, suggesting that each site may serve as reservoirs for HPV infection at other sites [23–27]. We also did not perform colposcopy on every participant nor at every visit and therefore could not evaluate the actual prevalence and incidence of histologically diagnosed cervical precancerous lesions.
In conclusion, Asian female youth with perinatally acquired HIV were at higher risk of having persistent HR-HPV infections and of acquiring new infections in anogenital compartments. Although working toward having primary prevention of cervical and other anogenital cancers through HPV vaccination programs in regional public health programs, secondary prevention of cervical cancer screening with cervical Pap smear and/or HPV testing can be implemented and immediately strengthened for adolescents and women who lack access to HPV vaccination. For both interventions, those living with HIV should be prioritized, among whom PHIV youth are at greater risk of persistent and incident HR-HPV infection. In order to prevent and eventually eliminate anogenital cancers among PHIV youth, public health programs in the Asia region must work more effectively with policy makers to implement these services.
Supplementary Material
Notes
Study Steering Committee. Sivaporn Gatechompol, Stephen Kerr, Chavalun Ruengpanyathip, HIV-NAT, Bangkok, Thailand; Kulkanya Chokephaibulkit, Manopchai Thamkhantho, Amphan Chalermchockcharoenkit, Sirintip Sricharoenchai, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; Rawiwan Hansudewechakul, Jullapong Achalapong, Vanichaya Wanchaitanawong, Chiangrai Prachanukroh Hospital, Chiangrai, Thailand; Dang Le Dunh Hanh, Dang Ngoc Yen Dung, Tran Dang Thang, Hung Vuong Hospital, Ho Chi Minh City, Vietnam; Dan Ngoc Hanh Tran, Khanh Huu Truong, Children’s Hospital 1, Ho Chi Minh City, Vietnam; Surasith Chaithongwongwatthana, Wichai Termrungruanglert, Surang Triratanachat, Sunee Sirivichayakul, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Joel M. Palefsky, University of California, San Francisco, USA; Nittaya Phanuphak, Nipat Teeratakulpisarn, Tippawan Pankam, Thai Red Cross AIDS Research Centre, Bangkok, Thailand; Annette Sohn, Jeremy Ross, Thida Singtoroj, Waropart Pongchaisit, Kamonrat Kosaphan, TREAT Asia/amfAR, The Foundation for AIDS Research, Bangkok, Thailand.
Acknowledgments. The authors thank the study participants, their families, the study staff, and Dr. Joel Palefsky (University of California, San Francisco) for their contributions to this research.
Disclaimer. The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.
Financial support. This work was supported by the US National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD073972), and additional support from LIFE+, Austria, through grants to TREAT Asia, a program of amfAR, The Foundation for AIDS Research, and SEARCH/Thai Red Cross AIDS Research Centre.
Potential conflicts of interest. A. H. S. has received research and travel funding to their institutions from ViiV Healthcare. All other authors report no potential conflicts. 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 article have been disclosed.
References
- 1. Sohn AH, Hazra R. Old problems for new providers: managing the postpediatric HIV generation. Clin Infect Dis 2017; 64:1113–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, Darragh TM. High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 1998; 12: 495–503. [DOI] [PubMed] [Google Scholar]
- 3. Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet 2013; 382:889–99. [DOI] [PubMed] [Google Scholar]
- 4. Kelly H, Weiss HA, Benavente Y, de Sanjose S, Mayaud P; ART and HPV Review Group Association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with HIV: a systematic review and meta-analysis. Lancet HIV 2018; 5:e45–58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Chokephaibulkit K, Kariminia A, Oberdorfer P, et al. ; TREAT Asia Pediatric HIV Observational Database Characterizing HIV manifestations and treatment outcomes of perinatally infected adolescents in Asia. Pediatr Infect Dis J 2014; 33:291–4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Picat MQ, Lewis J, Musiime V, et al. ; ARROW Trial Team Predicting patterns of long-term CD4 reconstitution in HIV-infected children starting antiretroviral therapy in sub-Saharan Africa: a cohort-based modelling study. PLoS Med 2013; 10:e1001542. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Sohn AH, Hazra R. The changing epidemiology of the global paediatric HIV epidemic: keeping track of perinatally HIV-infected adolescents. J Int AIDS Soc 2013; 16:18555. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. amfAR. Cervical Cancer, Human Papillomavirus (HPV), and HPV Vaccines in Southeast Asia. New York, 2016. Accessed 3 December 2019. Available at: https://www.amfar.org/uploadedFiles/_amfarorg/Articles/Around_The_World/TreatAsia/2016/hpvbrief1.pdf. [Google Scholar]
- 9. Kurman R, Solomon DT.. The Bethesda System for Reporting Cervical/Vaginal Cytologic Diagnoses. New York: Springer, 1994. [Google Scholar]
- 10. UNAIDS. AIDSinfo Asia and Pacific: People Living with HIV Available at https://aidsinfo.unaids.org. Accessed 3 June 2019.
- 11. Viseskul N, Fongkaew W, Settheekul S, Grimes RM. Factors related to sexual self-efficacy among thai youth living with HIV/AIDS. J Int Assoc Provid AIDS Care 2015; 14:423–7. [DOI] [PubMed] [Google Scholar]
- 12. Mu W, Zhao Y, Khoshnood K, et al. . Knowledge and perceptions of sexual and reproductive health and HIV among perinatally HIV-infected adolescents in rural China. AIDS Care 2015; 27:1137–42. [DOI] [PubMed] [Google Scholar]
- 13. Lolekha R, Boon-Yasidhi V, Leowsrisook P, et al. . Knowledge, attitudes, and practices regarding antiretroviral management, reproductive health, sexually transmitted infections, and sexual risk behavior among perinatally HIV-infected youth in Thailand. AIDS Care 2015; 27:618–28. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Kelly HA, Sawadogo B, Chikandiwa A, et al. ; HARP Study Group Epidemiology of high-risk human papillomavirus and cervical lesions in African women living with HIV/AIDS: effect of anti-retroviral therapy. AIDS 2017; 31:273–85. [DOI] [PubMed] [Google Scholar]
- 15. Camacho-Gonzalez AF, Chernoff MC, Williams PL, et al. . Sexually transmitted infections in youth with controlled and uncontrolled human immunodeficiency virus infection. J Pediatric Infect Dis Soc 2017; 6(3): e22–e9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Siegenbeek van Heukelom ML, Marra E, de Vries HJC, Schim van der Loeff MF, Prins JM. Risk factors for anal high-grade squamous intraepithelial lesions in HIV-positive MSM: is targeted screening possible? AIDS 2017; 31:2295–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Moscicki AB, Ellenberg JH, Farhat S, Xu J. Persistence of human papillomavirus infection in HIV-infected and -uninfected adolescent girls: risk factors and differences, by phylogenetic type. J Infect Dis 2004; 190:37–45. [DOI] [PubMed] [Google Scholar]
- 18. Travassos AG, Netto E, Xavier-Souza E, et al. . Predictors of HPV incidence and clearance in a cohort of Brazilian HIV-infected women. PLoS One 2017; 12:e0185423. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Salamanca SA, Sorrentino EE, Nosanchuk JD, Martinez LR. Impact of methamphetamine on infection and immunity. Front Neurosci 2014; 8:445. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Houlihan CF, Baisley K, Bravo IG, et al. . Rapid acquisition of HPV around the time of sexual debut in adolescent girls in Tanzania. Int J Epidemiol 2016; 45:762–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Hall MT, Simms KT, Lew JB, et al. . The projected timeframe until cervical cancer elimination in Australia: a modelling study. Lancet Public Health 2019; 4:e19–27. [DOI] [PubMed] [Google Scholar]
- 22. WHO Regional Office for South-East Asia. EPI Fact Sheet Thailand 2016 Accessed 17 October 2018 Available at: http://www.searo.who.int/immunization/data/thailand.pdf.
- 23. Goodman MT, Shvetsov YB, McDuffie K, et al. . Sequential acquisition of human papillomavirus (HPV) infection of the anus and cervix: the Hawaii HPV Cohort Study. J Infect Dis 2010; 201:1331–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Hernandez BY, McDuffie K, Zhu X, et al. . Anal human papillomavirus infection in women and its relationship with cervical infection. Cancer Epidemiol Biomarkers Prev 2005; 14:2550–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Guler T, Uygur D, Uncu M, et al. . Coexisting anal human papilloma virus infection in heterosexual women with cervical HPV infection. Arch Gynecol Obstet 2013; 288:667–72. [DOI] [PubMed] [Google Scholar]
- 26. Ortiz AP, Romaguera J, Pérez CM, et al. . Prevalence, genotyping, and correlates of anogenital HPV infection in a population-based sample of women in Puerto Rico. Papillomavirus Res 2016; 2:89–96. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Ramautarsing RA, Phanuphak N, Chaithongwongwatthana S, et al. . Cervical and anal HPV infection: cytological and histological abnormalities in HIV-infected women in Thailand. J Virus Erad 2015; 1:96–102. [PMC free article] [PubMed] [Google Scholar]
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