In an observational study of perinatally human immunodeficiency virus (HIV)–infected (PHIV) adolescents matched by age and sexual activity to uninfected females in Thailand and Vietnam, PHIV adolescents had higher rates of anogenital infection with high-risk human papillomavirus and abnormal cervical Pap smears.
Keywords: HIV, human papillomavirus, adolescent, perinatal, sexually transmitted infections
Abstract
Background
Infection with high-risk human papillomavirus (HR-HPV) may be higher in perinatally human immunodeficiency virus (HIV)–infected (PHIV) than HIV-uninfected (HU) adolescents because of long-standing immune deficiency.
Methods
PHIV and HU females aged 12–24 years in Thailand and Vietnam were matched by age group and lifetime sexual partners. At enrollment, blood, cervical, vaginal, anal, and oral samples were obtained for HPV-related testing. The Wilcoxon and Fisher exact tests were used for univariate and logistic regression for multivariate analyses.
Results
Ninety-three PHIV and 99 HU adolescents (median age 19 [18–20] years) were enrolled (June 2013–July 2015). Among PHIV, 94% were currently receiving antiretroviral therapy, median CD4 count was 593 (392–808) cells/mm3, and 62% had a viral load <40 copies/mL. Across anogenital compartments, PHIV had higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02). Higher proportions of PHIV had abnormal Pap smears (eg, atypical squamous cells of unknown significance [ASC-US], 12% vs 14%; low-grade squamous intraepithelial neoplastic lesions, 19% vs 1%). After adjusting for ever being pregnant and asymptomatic sexually transmitted infections (STI) at enrollment, PHIV were more likely to have HR-HPV than HU (odds ratio, 2.02; 95% confidence interval, 1.09–3.77; P = .03).
Conclusions
Perinatal HIV infection was associated with a higher risk of HR-HPV and abnormal cervical cytology. Our results underscore the need for HPV vaccination for PHIV adolescents and for prevention and screening programs for HPV and other STIs.
Human immunodeficiency virus (HIV) treatment coverage of the estimated 190000 adolescents aged 10–19 years living with HIV in the Asia-Pacific has been low, with less than one-third accessing appropriate antiretroviral therapy (ART) [1]. There is a growing generation of perinatally infected adolescents transitioning into adult life and at risk for other sexually transmitted infections (STIs) [2, 3]. One of the world’s most commonly acquired STIs is human papillomavirus (HPV), the primary cause of cervical and anal cancers, which has been shown to be more persistent and pathogenic in HIV-infected younger and older women [4–6].
Younger women may be more vulnerable to HPV due, in part, to immaturity of the cervical tissue as it transitions from metaplastic to squamous epithelium during that period of life [7]. While HIV-uninfected (HU) adolescents and young women frequently have regression of low-grade squamous intraepithelial neoplastic lesions (LSIL), HIV alters the dynamics of HPV infection, leading to prolonged infection and more frequent precancerous lesions. These risks remain even after immunologic recovery while on ART [8, 9] and may be greater in the current generation of perinatally HIV-infected young women, who were more likely to start ART later in childhood, compromising immune system development [10–12].
However, while vaccination now offers an effective prevention intervention in higher-income settings, most Asian countries lack a national policy to support HPV vaccination [13]. We conducted an observational study to assess the impact of perinatally acquired HIV (PHIV) on HPV coinfection and cervical cytologic and histologic outcomes among young Asian women.
METHODS
The HPV in Adolescents Study is a longitudinal, observational, cohort study in Thailand and Vietnam to compare patterns of acquisition and clearance of HPV infection among PHIV and HU females and males, and associated cervical cytology and histologic squamous intraepithelial neoplasia in females. The methods for the female component of this study are described below.
Study Participants
PHIV and HU female adolescents and young adults aged 12–24 years with a history of vaginal intercourse were recruited at 5 study sites: Thailand—HIV-NAT-Thai Red Cross AIDS Research Centre, and Siriraj Hospital Mahidol University both in Bangkok, and Chiang Rai Prachanukroh Hospital in Chiang Rai, and Vietnam—Children’s Hospital 1 and Hung Vuong Hospital, both in Ho Chi Minh City. All Thai sites and Children’s Hospital 1 were providing routine HIV care to the PHIV youth invited to participate in the study. PHIV and HU participants were matched by age group (12–15, 16–18, 19–21, 22–24 years) and number of lifetime partners (≤3 or >3). Participants were excluded if they were pregnant at the screening visit, if they had an untreated symptomatic STI (except genital warts), or had received prior doses of HPV vaccine and if they were unable to independently complete the study’s audio computer-assisted self-interview. Individuals were excluded if they were behaviorally HIV infected or if they were HIV uninfected with other chronic diseases or were using medications associated with compromised immune function.
Study Procedures
Potential study participants provided consent and were then screened at the local study sites. Eligible nonpregnant PHIV and HU females proceeded with baseline study visits that included clinical and sexual behavior assessments, blood testing (complete blood count, alanine transaminase, creatinine, fasting lipids, rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) tests with confirmatory test, CD4 and HIV RNA for PHIV, HIV antibody for HIV uninfected, urine collection (pregnancy), oral rinse, and anogenital evaluation.
Vaginal, cervical, and anal samples were obtained and placed in separate liquid-based cytology (LBC) containers (ThinPrep PAP test, Hologic, Inc., Massachusetts) for processing. Oral wash and cytology fluid were stored at −20°C to −70°C prior to shipment to the study’s central laboratory at the Thai Red Cross AIDS Research Centre. Other routine blood, urine pregnancy, and HIV-related testing (antibody, CD4, HIV RNA) were performed at study site laboratories.
HPV and Other STI Testing
Cervical cytology and histology were evaluated at Chulalongkorn University, Bangkok, Thailand. Chlamydia and gonorrhea (Abbott RealTime CT/NG assay, Abbott Molecular Inc., Illinois; Cobas4800 CT/NG test, Roche Molecular Systems, Inc., New Jersey), herpes simplex virus 2 (HSV-2; HSV I & II Typing Real Time PCR kit, Shanghai ZJ Bio-Tech Co. Ltd.), syphilis serology screening (RPR, Becton, Dickinson and Company, Maryland; confirmation testing TP-PA, Fujirebio Inc., Tokyo, Japan), and HPV-related testing were conducted at the central laboratory.
LBC fluid from the 3 anogenital compartments and oral rinses were tested using the LINEAR ARRAY test (LA HPV GT, Roche Molecular Systems, Inc.) to identify 13 high-risk HPV (HR-HPV) DNA genotypes (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) and 24 other genotypes (6, 11, 26, 40, 42, 53, 54, 55, 61, 62, 64, 66, 67, 69, 70, 71, 72, 73 [MM9], 81, 82 [MM4], 83 [MM7], 84 [MM8], IS39, CP6108). Cervical LBC fluid samples were used to detect E6 and E7 mRNA by flow cytometric analysis (HPV OncoTect E6, E7 mRNA test, incellDx, CA) for 14 HR-HPV types (16, 18, 31, 33, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73).
Cytology and Histology
Cervical cytology results were classified using the 2001 Bethesda system as normal, atypical squamous cells of unknown significance (ASC-US), atypical squamous cells cannot exclude high-grade squamous intraepithelial lesion (ASC-H), LSIL, high-grade squamous intraepithelial lesion (HSIL), or carcinoma [14]. Histology results were categorized as atypia, cervical intraepithelial neoplasia (CIN) 1, CIN 2, CIN 3, carcinoma in situ, and invasive carcinoma.
Participants meeting colposcopy referral criteria were scheduled for additional follow-up. Specifically, this included those with ASC-US and concomitant infection with a HR-HPV type or detection of E6/E7 mRNA, LSIL, ASC-H, HSIL, and atypical glandular cells or carcinoma on cervical cytology. Cervicovaginal abnormalities identified during a colposcopy visit were biopsied for histologic analysis.
Ethics Reviews
The study protocol and informed consent and assent documents were approved by the institutional review boards at the coordinating center (amfAR/TREAT Asia) and at each participating study site. Consent procedures were conducted in the local language (Thai or Vietnamese) by trained study staff. Guardian consent and adolescent assent procedures were followed for participants aged <18 years who could not legally consent for themselves. These participants were formally consented for ongoing study participation after turning 18 or otherwise reaching the age of maturity according to local law.
Statistical Methods
Power calculations were based on the prevalence of vaginal HPV in HIV-positive (73%) and HU (43%) female adolescents in the US REACH (Reaching for Excellence in Adolescent Care and Health) cohort [15]. Assuming a baseline prevalence of 40% in the HU adolescents, with 90 participants in each group we would have 80% power to detect a 21% difference in prevalence between groups, with 80% power at a 2-sided significance level of 5%. Categorical covariates were compared between study groups using a Wilcoxon test for continuous covariates and Fisher exact test for categorical covariates. Logistic regression was used to assess the association between demographic and behavioral characteristics and the presence of any cervical, vaginal, or anal HR-HPV. Factors with P < .1 in univariate models were adjusted for in a multivariate analysis. Statistical analysis was performed with Stata, version 14 (Statacorp LP, College Station, Texas).
RESULTS
Participant Characteristics
Ninety-three PHIV and 99 HU adolescents with a median age of 19 (18–20) years were enrolled between June 2013 and July 2015. PHIV participants were less likely to live with biological parents (26% vs 62%) and more likely to be single or double orphans (81% vs 24%). Approximately equal proportions of both groups were living with a partner or husband (26% vs 19%) and working to support themselves (45% vs 31%). The majority were currently in or had completed secondary school (77% vs 70%). Among PHIV participants, 94% were currently receiving first- or second-line ART, with a median duration from ART start of 4.1 (interquartile range [IQR], 2.5–6.5) years. The median CD4 cell count at enrollment was 593 (392–808) cells/mm3, and 62% had a viral load <40 copies/mL. One-third (37%) reported some difficulties with adherence, and the median adherence rate in the previous month was 97%.
Sexual Behaviors and Substance Use
In both groups, the median (IQR) number of lifetime partners was 2 (1–3), and partners in the previous 6 months was 1 (1–1); 4% of PHIV and 1% of HU participants reported ever having receptive anal sex, and approximately 22% of both groups reported ever having receptive oral sex (Table 1). More PHIV than HU participants reported consistently using condoms with vaginal sex in the past 6 months (33% vs 11%); the majority in both groups reported sometimes or never (65% vs 85%) using condoms. One-third of PHIV and 44% of HU adolescents reported previous pregnancies.
Table 1.
Participant Characteristics at Study Entry (N = 192)
| Characteristic | Total (n = 192) | Perinatally HIV Infected (n = 93) | HIV Uninfected (n = 99) | P Value |
|---|---|---|---|---|
| Age, years | 19 (18–20) | 19 (17–20) | 19 (18–20) | .36 |
| Ethnicity | 1.0 | |||
| Thai | 177 (92%) | 86 (92%) | 91 (92%) | … |
| Vietnamese | 15 (8%) | 7 (8%) | 8 (8%) | … |
| Living situation | <.001 | |||
| One or both parents | 84 (44%) | 24 (26%) | 60 (61%) | … |
| Relatives | 44 (23%) | 33 (35%) | 11 (11%) | … |
| Partner | 43 (22%) | 24 (26%) | 19 (19%) | … |
| Alone | 15 (8%) | 8 (9%) | 7 (7%) | … |
| Other, did not answer | 6 (3%) | 4 (4%) | 2 (2%) | … |
| Orphan status | <.001 | |||
| Not an orphan | 87 (45%) | 13 (14%) | 74 (75%) | … |
| Maternal or paternal orphan | 55 (29%) | 34 (37%) | 21 (21%) | … |
| Double orphan | 44 (23%) | 41 (44%) | 3 (3%) | … |
| Unknown | 6 (3%) | 5 (5%) | 1 (1%) | … |
| Current/highest education | .36 | |||
| Primary school | 20 (10%) | 10 (11%) | 10 (10%) | … |
| Secondary school | 141 (73%) | 72 (77%) | 69 (70%) | … |
| Beyond secondary school | 30 (16%) | 11 (12%) | 19 (19%) | … |
| Employment/school | .003 | |||
| Currently working | 73 (38%) | 42 (45%) | 31 (31%) | … |
| In school | 78 (41%) | 41 (44%) | 37 (37%) | … |
| Neither | 40 (21%) | 10 (11%) | 30 (30%) | … |
| Type of sexual relationships | … | |||
| Female–Male | 184 (99%) | 88 (100%) | 96 (99%) | 1.00 |
| Female–Female | 13 (7%) | 8 (9%) | 5 (5%) | .39 |
| Did not answer | 7 (4%) | 5 (5%) | 2 (2%) | … |
| Prior sexual activity by route | ||||
| Anal receptive | 5 (3%) | 4 (4%) | 1 (1%) | .20 |
| Oral receptive | 42 (22%) | 19 (21%) | 23 (23%) | .73 |
| Lifetime partners | 2 (1–3) | 2 (1–3) | 2 (1–3) | .76 |
| Partners in past 6 months | 1 (1–1) | 1 (1–1) | 1 (1–1) | .74 |
| Monthly frequency of sex in past 3 months | .34 | |||
| ≤5 times | 107 (56%) | 56 (60%) | 51 (52%) | … |
| 6–10 times | 32 (17%) | 11 (12%) | 21 (21%) | … |
| 11–20 times | 13 (7%) | 5 (5%) | 8 (8%) | … |
| >20 times | 21 (11%) | 11 (12%) | 10 (10%) | … |
| Did not answer | 19 (10%) | 10 (11%) | 9 (9%) | |
| Condom use with vaginal sex in past 6 months | <.001 | |||
| Always | 42 (22%) | 31 (33%) | 11 (11%) | … |
| Sometimes | 93 (48%) | 50 (54%) | 43 (43%) | … |
| Never | 52 (27%) | 10 (11%) | 42 (42%) | … |
| No recent sex | 5 (3%) | 2 (2%) | 3 (3%) | … |
| Ever been pregnant | 75 (39%) | 31 (33%) | 44 (44%) | .14 |
| Asymptomatic sexually transmitted infections at baseline | ||||
| Chlamydia trachomatis | 44 (23%) | 24 (26%) | 20 (20%) | .39 |
| Neisseria gonorrhoea | 5 (3%) | 5 (5%) | 0 (0%) | .03 |
| Syphilis | 4/190 (2%) | 2/92 (2%) | 2/98 (2%) | 1.0 |
| Herpes simplex virus 2 | 3 (2%) | 0 (0%) | 3 (3%) | .25 |
| Any cervical HPV | 98 (51%) | 58 (62%) | 40 (40%) | .003 |
| Any cervical HR HPV | 69 (36%) | 40 (43%) | 29 (29%) | .05 |
| Any vaginal HPV | 110/190 (58%) | 62/91 (68%) | 48 (48%) | .01 |
| Any vaginal HR HPV | 80/190 (42%) | 45/91 (49%) | 35 (35%) | .06 |
| Any anal HPV | 94/191 (49%) | 54 (58%) | 40/98 (41%) | .02 |
| Any anal HR HPV | 62/191 (32%) | 39 (42%) | 23/98 (23%) | .008 |
| Any anogenital HPV | 133 (69%) | 74 (80%) | 59 (60%) | .003 |
| Any anogenital HR HPV | 99 (52%) | 56 (60%) | 43 (43%) | .02 |
| Any oral HPV | 18/190 (9%) | 10/91 (11%) | 8 (8%) | .62 |
| Any oral HR HPV | 9/190 (5%) | 5/91 (5%) | 4 (4%) | .74 |
Characteristics are described as median (interquartile range or N [%]). Percentages are rounded and may not total 100%. Where test results were invalid or not performed, the denominator is shown.
Abbreviations: HIV, human immunodeficiency virus; HPV, human papillomavirus; HR, high risk.
Fewer PHIV participants had tried alcohol (77% vs 90%), cigarettes (29% vs 44%), or other drugs (8% vs 19%); 1 PHIV participant reported ever having injected drugs (Supplementary Table 1). Similar proportions (17% vs 20%) reported having unsafe sex after using alcohol or other substances.
HPV and Asymptomatic STI at Study Entry
Infection with Chlamydia trachomatis was the most common prevalent asymptomatic STI, present in 26% of PHIV and 20% of HU adolescents. A significantly higher proportion of PHIV participants had gonorrhea (5% vs 0%, P = .03), 2% of both groups had a reactive VDRL (confirmed by Treponema pallidum hemagglutination assay testing), and no PHIV but 3% of HU participants had HSV-2 infection.
Cervical HPV infection of any type was more prevalent in the PHIV group than in the HU group: 62% vs 40% had any HPV detected (P = .003), and 43% vs 29% had at least 1 HR-HPV genotype detected (P = .05). Similar levels of HR-HPV detection were found in samples collected from the vagina (49% vs 35%), but a significantly higher proportion of PHIV participants had HR-HPV detected in the anus (42% vs 23%, P = .008; Table 1). In any anogenital compartment, PHIV participants had significantly higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02) than HU participants. HPV infection in the oral cavity was present in 11% of PHIV and 8% of HU adolescents (P = .64). The most commonly detected HR-HPV genotypes in the cervix, vagina, and anus included types 16, 18, 52, and 59 (Figure 1).
Figure 1.
Prevalence of individual high-risk human papillomavirus subtypes by anatomical site. Abbreviations: HIV, human immunodeficiency virus; HIV-neg, HIV uninfected; HPV, human papillomavirus; PHIV, perinatally HIV infected.
Cervical Cytology
Normal cervical cytology was present in 67% of PHIV participants and 84% of HU participants (Figure 2). Higher proportions of PHIV participants had abnormal Pap smears compared to HU participants (ASC-US, 12% vs 14%; LSIL, 19% vs 1%; HSIL, 1% vs 1%; ASC-H, 1% vs 0; P < .001). Of the 40 (28 PHIV, 12 HU) participants who met criteria for referral, 23 (58%; 19 PHIV, 4 HU) underwent colposcopic examination with or without biopsy within 24 weeks of their baseline cytology visit (Supplementary Table 2). Among those who did not have colposcopies, 9 were PHIV (5 with ASC-US; 1 with ASC-H; 3 with LSIL) and 8 were HU (7 with ASC-US; 1 with HSIL). Reasons for missed colposcopies included delayed referrals (29%) and temporary or permanent loss to follow-up (42%). The colposcopic findings among the PHIV participants included 42% with normal evaluations, 26% with condyloma acuminata, 16% with changes consistent with HPV infection, and 11% with CIN 1. Three (75%) of the 4 HU participants with colposcopies had HPV-related changes. Of the 9 (39%) participants who had biopsies taken, 3 had CIN 1 and 1 had CIN 3; all were PHIV.
Figure 2.
Cervical cytology results. P for difference between groups <0.001. Abbreviations: ASC-H, atypical squamous cells, cannot exclude HSIL; ASC-US, atypical squamous cells of unknown significance; HIV, human immunodeficiency virus; HIV-neg, HIV uninfected; HSIL, high-grade squamous intraepithelial lesion; LSIL, low-grade squamous intraepithelial lesion; PHIV, perinatally HIV infected.
Association Between Participant Demographic and Behavioral Characteristics and HR-HPV in Anogenital Compartments
We used logistic regression to assess associations between participant characteristics and behaviors and any detected HR-HPV infection in the cervix, vagina, or anus (Table 2). In a univariate analysis, HIV status, increasing number of lifetime partners, and having an asymptomatic STI diagnosed at enrollment were associated with a significantly higher odds of having HR-HPV, while ever being pregnant was associated with a reduced odds. After adjusting for ever having been pregnant and having an asymptomatic STI at enrollment in a multivariate model, PHIV participants were more likely to have HR-HPV than HU adolescents (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.09–3.77; P = .03). Overall, compared to those with 1 lifetime partner, those with ≥2 partners had an increased odds of HR-HPV infection (OR, 3.46; 95% CI, 1.78–6.71; P < .001). In a subgroup analysis of HIV-specific characteristics in PHIV participants, we found no associations between HR-HPV and current or nadir CD4 count or current viral load.
Table 2.
Factors Associated With Any High-Risk Human Papillomavirus Genotype at Baseline Study Visit
| Univariate | Multivariate | |||
|---|---|---|---|---|
| Characteristic | OR (95% CI) | P Value | OR (95% CI) | P Value |
| Study group | .02 | .03 | ||
| HIV uninfected | 1 (ref) | 1 (ref) | ||
| Perinatally HIV infected | 1.97 (1.11–3.50) | 2.02 (1.09–3.77) | ||
| Age (years) | .83 | |||
| 13–16 | 1.34 (0.52–3.43) | … | ||
| 17–19 | 1.12 (0.61–2.05) | … | ||
| 20–24 | 1 (ref) | … | ||
| Orphan status | .57 | |||
| Not an orphan | 1 (ref) | … | ||
| Maternal orphan | 1.79 (0.71–4.51) | … | ||
| Paternal orphan | 0.68 (0.29–1.56) | … | ||
| Double orphan | 2.07 (0.98–4.39) | … | ||
| Unknown | 0.21 (0.02–1.91) | … | ||
| Highest education | .55 | |||
| Primary school | 1 (ref) | … | ||
| Secondary school | 1.28 (0.50–3.27) | … | ||
| Beyond secondary school | 1.83 (0.58–5.76) | … | ||
| Condom use with vaginal sex in past 6 months | .45 | |||
| Always/no sex in past 6 months | 1 (ref) | … | ||
| Sometimes/never | 1.29 (0.67–2.49) | … | ||
| Employment/school status | .48 | |||
| In school | 1 (ref) | … | ||
| Working | 1.48 (0.78–2.82) | … | ||
| Neither | 1.27 (0.59–2.74) | … | ||
| Used alcohol in past 3 months | 1.03 (0.58–1.82) | .92 | … | |
| Smoked in past 3 months | 1.02 (0.42–2.43) | .97 | … | |
| Used other drugs in past 3 months | 1.91 (0.46–7.89) | .36 | … | |
| Lifetime number of sexual partners | <.001 | <.001 | ||
| 1 | 1 (ref) | 1 (ref) | ||
| ≥2 | 3.90 (2.09–7.28) | 3.46 (1.78–6.71) | ||
| Sexual partners in past 6 months | .28 | |||
| None | 1 (ref) | … | ||
| 1 | 0.73 (0.24–2.20) | … | ||
| ≥2 | 1.88 (0.39–9.01) | … | ||
| Ever had unsafe sex after using alcohol or other drugs | 1.59 (0.76–3.34) | .21 | … | |
| Ever been pregnant | 0.61 (0.34–1.09) | .09 | 0.61 (0.32–1.15) | .12 |
| Asymptomatic sexually transmitted infection at week 0 visit | 2.72 (1.38–5.36) | .003 | 1.99 (0.96–4.14) | .06 |
| HIV-specific covariates (perinatally HIV infected only) | ||||
| HIV-RNA >40 copies/mL | 1.77 (0.73–4.28) | .20 | … | |
| Current CD4 count (cells/mm3) | .31 | |||
| ≤350 | 1 (ref) | … | ||
| 351–500 | 0.48 (0.12–1.98) | … | ||
| >500 | 1.18 (0.40–3.50) | … | ||
| Nadir CD4 count (cells/mm3) | .25 | |||
| <200 | 1 (ref) | … | ||
| 201–500 | 0.51 (0.17–1.57) | … | ||
| >500 | 0.41 (0.13–1.22) | ... | ||
Human papillomavirus detected at cervix, vagina, and/or anus.
Abbreviations: CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio.
DISCUSSION
Half of our cohort had prevalent HR-HPV infection, and PHIV adolescent females were more frequently infected with HR-HPV across anogenital compartments and had greater cervical dysplasia on Pap smear than HU adolescents (60% vs 43%). Although our rate of anogenital HR-HPV infection among PHIV participants is similar to those reported among older HIV-infected women and behaviorally HIV-infected youth from other countries [16–19], it is 2–3 times that observed in older HIV-infected Thai women (19%–35% at median ages of 25–40 years) [20–22]. The scale of this difference emphasizes the greater vulnerability of Asian PHIV adolescents to long-term cancer risk. One-third of our adolescents had abnormal cervical cytology, which was consistent with an earlier US PHIV cohort (30%; mean age 19 years) [23] but higher than a parenterally infected Romanian cohort (25%; mean age 23 years) [24]. Furthermore, on colposcopy, condyloma acuminata and CIN 1 and CIN 3 on either visual inspection or biopsy were only detected among PHIV participants (42% vs 0% of those evaluated), raising concerns about the relative severity of disease they experience.
Although recognized as the world’s most common STI, the global impact of HPV infection is largely hidden until it causes anogenital and oral cancers decades later. Younger women are more likely to acquire initial and multiple genotype infections due, in part, to cervical ectopy [15, 25]. However, these early infections generally self-resolve, which has led to recommendations to screen them less frequently and to avoid aggressive management for less advanced dysplasia [26]. However, HIV’s weakening of cellular immunity is considered a key reason why it is associated with more rapid HPV acquisition after new HIV infection and a 2- to 22-fold higher incidence of invasive cervical cancer [27, 28]. Perinatally acquired HIV and its associated life-long impact on the immune system may consequently put infected adolescents and young women at greater risk of HPV-related diseases.
PHIV youth have been reported to have slower pubertal maturity, later sexual debut, and higher condom use than HU youth [29–31]. This has made comparisons to sexual health outcomes of the uninfected or the behaviorally infected more complicated, and STI frequencies have been reported to be lower among the perinatally infected [32]. However, when matched for behavior, PHIV females in our study had higher baseline HPV and asymptomatic gonorrhea infection than HU females, despite reporting more regular condom use and less frequent substance use.
There are varying data on how ART impacts the natural history of HPV infection in terms of acquisition, persistence, and disease progression. Studies examining associations with any or longer durations of therapy are confounded by adherence patterns, but ART that effectively controls HIV and leads to immune recovery appears to be beneficial [16, 27, 32]. Although we observed no positive or negative association with ART outcomes, almost all of our PHIV participants were on ART and had high levels of immune reconstitution (median CD4, 593 cells/mm3), although HIV control in terms of viral suppression was moderate (63%). The small numbers of patients with immune deficiency may have prevented us from being able to detect an association.
HPV vaccination using the quadrivalent vaccine has been shown in the IMPAACT P1085 study to be 90%–100% immunogenic in PHIV children and young adolescents aged 7–12 years with CD4 levels above 15%, but other studies have reported that responses may be reduced in the context of unsuppressed HIV [33–35]. Current recommendations of the Advisory Committee on Immunization Practices are to use a 3-dose series in those with HIV [36]. Unfortunately, the vaccines that can prevent the consequences of HPV are less accessible in the regions where most PHIV youth reside and often do not include catch-up vaccine programs for older adolescents [37]. Thailand started a national HPV vaccination program in August 2017 that provides access to females aged 10–12 years and enrolled in primary school (grade 5) [38, 39]. While an important step forward, this misses the vast majority of PHIV adolescents who have already aged out of this group, such as in our cohort where the majority had evidence of current HR-HPV infection. In addition to implementation of early vaccination programs, supplemental approaches to offer catch-up vaccine to older adolescents, such as Malaysia’s program that includes 18-year-olds, are essential if those at greater risk for HPV-related cancers are to be protected [13].
There were limitations in both the conduct of the study and the interpretation of our results. We were unable to enroll younger adolescents, which restricts the generalizability of our findings. Since consent for legal minors aged <18 years required admission of sexual activity, the social and cultural stigma against premarital sexual debut was viewed by site investigators as a deterrent. Social desirability bias could have impacted the reliability of our self-reported sexual behavior risks. We did not evaluate 42% of those meeting colposcopy referral criteria within 24 weeks of their cytology visit. In our routine clinical care settings, colposcopy referrals are even less consistently completed, further emphasizing the importance of preventive vaccination. Importantly, cross-sectional studies of HPV infection do not indicate the duration of infection, which plays a key role in the development of dysplasia. While we attempted to capture risk factors known to be related to both infections in sufficient detail, and our regression analysis adjusted for potential confounders derived from a careful review of the HPV and HIV literature, there remains a risk of unmeasured confounding. Given our pilot data and previous studies demonstrating associations in adults, we believe there is sufficient rationale for the associations we have observed, but additional follow-up to monitor for persistence vs clearance will facilitate further interpretation of the natural history of HPV in this cohort.
Our study showed that PHIV participants in Thailand and Vietnam had higher rates of HR-HPV infection and cervical dysplasia than HU adolescents and young women after matching for age and sexual behavior. While HPV vaccination is the optimal solution to prevent anogenital cancers, the lack of access to HPV vaccines in low- and middle-income countries makes screening to identify those in need of intervention an essential component of comprehensive HIV care for young women. Our results underscore the need for prevention and screening for HPV and other STIs in Asian PHIV adolescents.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Presented in part: Conference on Retroviruses and Opportunistic Infections. Seattle, Washington, 23–26 February 2015. Abstract 943.
Notes
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 National Institutes of Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD073972), with 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 her institution from ViiV Healthcare. All remaining 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.
Study steering committee members. 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; 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.
Contributor Information
HPV in Adolescents Study:
Sivaporn Gatechompol, Stephen Kerr, Chavalun Ruengpanyathip, Kulkanya Chokephaibulkit, Manopchai Thamkhantho, Amphan Chalermchockcharoenkit, Sirintip Sricharoenchai, Rawiwan Hansudewechakul, Jullapong Achalapong, Vanichaya Wanchaitanawong, Dang Le Dunh Hanh, Dang Ngoc Yen Dung, Tran Dang Thang, Dan Ngoc Hanh Tran, Khanh Huu Truong, Surasith Chaithongwongwatthana, Wichai Termrungruanglert, Surang Triratanachat, Sunee Sirivichayakul, Joel M Palefsky, Nittaya Phanuphak, Nipat Teeratakulpisarn, Tippawan Pankam, Annette Sohn, Jeremy Ross, Thida Singtoroj, Waropart Pongchaisit, and Kamonrat Kosaphan
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