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Incidence, Clearance, and Persistence of Anal Human Papillomavirus in Men Who Have Sex With Men Living With Human Immunodeficiency Virus: Implications for Human Papillomavirus Vaccination

Ong, Jason J. PhD*†‡; Walker, Sandra DPsych; Grulich, Andrew PhD§; Hoy, Jennifer MBBS; Read, Tim R.H. PhD*‡; Bradshaw, Catriona PhD*‡; Chen, Marcus PhD*‡; Garland, Suzanne M. MD**††; Cornall, Alyssa PhD**††; Hillman, Richard MD‡‡; Templeton, David J. PhD§§§¶¶; Hocking, Jane PhD***; Eu, Beng MBBS†††; Tee, BK MBBS‡‡‡; Chow, Eric P.F. PhD*‡; Fairley, Christopher K. PhD*‡

Author Information
Sexually Transmitted Diseases: April 2019 - Volume 46 - Issue 4 - p 229-233
doi: 10.1097/OLQ.0000000000000958
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Men who have sex with men (MSM) living with human immunodeficiency virus (HIV) are disproportionately affected by anal cancer which is the most common non–acquired immune deficiency syndrome-defining malignancy affecting this population.1 High-risk human papillomavirus (HRHPV) are associated with anal cancer,2 particularly human papillomavirus (HPV) 16 and 18.1,3,4 The prevalence of anal HPV 16 and 18 in MSM living with HIV has been estimated to be 35.4% (95% confidence interval [CI], 32.9–37.9) and 18.6% (95% CI, 12.8–24.4), respectively, in a systematic review.1

Understanding the burden of HPV informs the value of preventive interventions like HPV vaccination. Since 2006, prophylactic HPV vaccination has been available and is highly effective in protecting against HPV types included in the vaccine in people not previously infected.5 Three HPV vaccines are available which provide protection against a variety of HPV types: bivalent (types 16, 18), quadrivalent (types 6, 11, 16, 18), and nonavalent (types 6, 11, 16, 18, 31, 33, 45, 52, 58) vaccines. Although increasing numbers of cross-sectional studies have been published on anal HPV prevalence among MSM,1,6 there are still limited numbers of longitudinal studies among MSM living with HIV, with even fewer reported from the Asia-Pacific region.7–9 As prevalence of HPV-related disease is higher among MSM living with HIV, further understanding of the incidence, persistence, and clearance of specific HPV types in MSM living with HIV may assist in determining the cost-effectiveness of HPV vaccination for men living in these regions. Not only are regional differences in HPV distribution important but age may also play an important factor in the incidence of HPV types.10,11

Due to their relatively high risk of developing HPV-related anal cancer, MSM living with HIV have the greatest potential benefit from HPV vaccination compared with the general population. We used the data from the Anal Cancer Examination study, a prospective anal cancer screening study of MSM living with HIV who contributed 2 anal swabs for HPV detection at baseline and 2 years later. The aim of this study was 2-fold. First, because there are limited data in the literature to understand the burden of anal HPV in MSM living with HIV, we reported anal HRHPV prevalence, incidence, persistence, and clearance. Second, using these data, we calculated the incidence of HPV vaccine-preventable types and the proportion of men who may have benefited from HPV vaccination if they did not have active infection with the HPV vaccine type at baseline. Our hypothesis was that there are a significant number of MSM living with HIV that do not have infection with all HPV vaccine types at baseline and thus may still benefit from HPV vaccination to reduce their risk of HPV-related cancers.

METHOD

Study Population

The Anal Cancer Examination study was a prospective cohort study which recruited 327 MSM living with HIV between 2013 and 2014 from a sexual health clinic, 2 high caseload general practice clinics and a hospital infectious diseases clinic, in Melbourne, Australia with a follow-up period of 2 years from recruitment until 2016.12 Men who have sex with men living with HIV older than 5 years and who were not diagnosed with anal cancer were invited to participate. These men completed questionnaires and had anal swabs taken twice by their clinician: at baseline and at their follow up visit 2 years later. The anal swab (Floqswab; Copan Flock Technologies) was inserted 3 to 5 cm into the anus and rotated 360 degrees while withdrawing over 15 seconds.

Laboratory Methods

Anal swabs were collected from each clinical site once a week, and swabs were rotated in 1 mL of RNAlater preservative solution (Ambion, Austin, TX) by the researcher. An aliquot of 200 μL was extracted by the automated MagNA Pure 96 isolation and purification system (Roche Diagnostics, Mannheim, Germany) using the DNA and viral NA (nucleic acid) small-volume isolation kit. After nucleic acid isolation, all samples were initially assessed for DNA adequacy with a quantitative PCR for a 260-bp fragment of the human beta-globin gene.13 Samples were subjected to PCR amplification of a 450-bp fragment of the HPV L1 gene using consensus primers PGMY09/11.14 Amplicons were detected by PCR ELISA (Roche Diagnostics) using biotin-labeled generic HPV detection probes, as described previously.13,15 Samples that were HPV-positive by PCR-ELISA were subsequently genotyped by linear array HPV Genotyping Test (Roche Diagnostics), with an additional type-specific quantitative PCR assay to confirm the presence of HPV52 where required.16 Samples that were HPV-positive by PCR-ELISA but negative by linear array were genotyped using the more sensitive RHA kit HPV SPF10-LiPA-25, version 1 and SPF+ (Labo Bio-Medical Products BV, Rijswijk, the Netherlands). The SPF+ strips are capable of detecting the following additional genotypes: HPV26, 30, 55, 61, 632, 64, 67, 69, 71, 82 to 87, 89 to 91. Samples that were PGMY09/11 ELISA-negative were retested on the more sensitive DNA ELISA kit HPV SPF10, version 1 (Labo Bio-Medical Products BV). SPF10 ELISA-positive samples were genotyped using the RHA kit HPV SPF10-LiPA-25 and SPF+. Samples that were negative for the 260 bp beta-globin amplicon were retested using a more sensitive beta-globin assay with a shorter 110-bp target, as previously described.17 Only HPV genotypes common to both genotyping assays were considered in the analysis; in total, 34 HPV types were assessed (6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 73, 82, 83, 84, 89) though the focus of this article is on HRHPV types (16, 18, 31, 33, 35, 45, 51, 52, 56, 58, 59, and 68.18 Samples that were beta-globin–negative and HPV-negative after all testing were considered unassessable and omitted from further analysis.

Measurements

For each HPV type, prevalent HPV at each visit was defined as detection of HPV at the anus at that visit. Prevalence was defined as the percentage of men with anal HPV at that visit, out of all men with valid test results. Type-specific incident HPV was defined as the detection of anal HPV at the date of the 2-year follow-up visit in a person who was negative for that type at the baseline visit, consistent with measurement in other research.19 The type-specific incidence rate is defined as the number of incident events divided by the person-time at risk. Persistent HPV was defined as detection of the same HPV type at both baseline and 2 years. Human papillomavirus clearance was defined as the absence of an HPV type at 2 years which was detected at baseline. We defined vaccine-preventable types as HPV 16 and 18 (bivalent), HPV 6, 11, 16, and 18 (quadrivalent) and HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 (nonavalent).

Statistical Analyses

Descriptive statistics were calculated to summarize the sociodemographic characteristics of men in the study. We calculated the prevalence, incidence, persistence, and clearance of individual HPV types with 95% confidence intervals. To estimate the potential cancer prevention benefit of HPV vaccines in this population, we calculated the incidence of HRHPV vaccine-preventable types; and the proportion of men who had at least 1 incident HRHPV vaccine-preventable type 2 years later, stratified by age groups. We tested for statistically significant differences across age groups using a nonparametric test for trend, that is, extension of the Wilcoxon rank-sum test. All statistical analyses were performed using STATA (Stata Statistical Software, version 13. College Station, TX).20

Ethics approval for this study was granted by the Alfred Health Human Ethics Committee, Victoria, Australia (number 146/12).

RESULTS

Of 327 men who had baseline HPV swabs, 85% (n = 279) returned for their visit at 2 years and contributed an anal swab. Nine swabs were unassessable, leaving 270 assessable swabs at the final visit. Of these 270 men, 15 had an unassessable baseline swab, so swabs from 255 men (78%) were included for analysis (ie, assessable baseline and final swab). The median duration of time from baseline to final follow-up was 1.99 years (interquartile range [IQR], 1.84–2.17 years) with participants contributing a total of 488.9 person-years of follow-up over the study period.

Demographics

Table 1 summarizes the key demographics of the study population at baseline. In brief, the median age of participants was 50 years (IQR, 44–56 years) and 68% of men were born in Australia. Almost all were on antiretroviral therapy (94%), and the median duration since HIV diagnosis was 12 years (IQR, 6–21 years).

TABLE 1
TABLE 1:
Sociodemographic Characteristics and HIV-related Parameters of MSM Living With HIV at Baseline

At the 2-year follow up, half of participants (56%; 95% CI, 49–62; 119 of 214) reported receptive anal sex with a new partner during the study period (ie, within the preceding 2 years). Of 255 men, the mean number of new partners involving receptive anal sex was 7.5 (SD, 25.7).

HPV Prevalence at Baseline and Incident HPV

Of 255 men, 189 (74%; 95% CI, 68–79) had at least 1 HPV type detected in their anus at baseline, 140 (55%; 95% CI, 49–61) had at least 1 HRHPV type detected and 61 (24%; 95% CI, 19–30) had HPV 16. Of 189 men with detectable anal HPV, 156 (83%; 95% CI, 76–88) had multiple HPV types present at baseline. The median number of HPV types detected at baseline was 2 (IQR, 0–4) with a maximum of 13. Table 2 shows that the types with the highest incidence included: HPV 53 (6.5 cases per 100 person-years), HPV 16 (4.9 of cases per 100 person-years), and HPV 51 (4.5 cases per 100 person-years). The proportion of men with at least 1 new HRHPV type on follow-up for the bivalent and quadrivalent vaccine was 10.2% (95% CI, 6.8–14.6; 26 of 255) and for the nonavalent vaccine was 29.4% (95% CI, 23.9–35.4; 75 of 255).

TABLE 2
TABLE 2:
Prevalence and Incidence of Anal HRHPV Types in MSM Living With HIV in Melbourne (N = 255)

Persistence and Clearance of HPV

After 2 years of follow-up, 149 (58%; 95% CI, 52–65) had at least 1 HRHPV, and 71 (28%; 95% CI, 22–34) had HPV types 16, 18, or both detected. Table 3 demonstrates that the most frequently persisting HRHPV types included: HPV 16 (67%), 51 (55%), and 45 (52%), corresponding to the lowest clearance rates for these types.

TABLE 3
TABLE 3:
Persistence and Clearance of HRHPV Types in MSM Living With HIV in Melbourne (N = 255)

Potential Cancer Prevention Benefit From HPV Vaccines

Table 4 estimates the percentage of men in each age group that may have potentially benefitted from HPV vaccination at baseline (ie, no vaccine-preventable HRHPV types or did not have all vaccine-preventable HRHPV types). We also calculated the percentage of men who had incident HRHPV after 2 years follow-up (ie, the missed opportunity to avert these HRHPV infections if they were vaccinated at baseline). We show that more than half of men did not have any vaccine-preventable HPV types at baseline, and virtually all men did not have all vaccine-preventable HPV types, so may potentially derive some cancer-protection from HPV vaccination. Combining results from all age groups in Table 2, about 1 in 10 men (10.2% of men; 95% CI, 6.8–14.6; 26 of 255) would have potentially avoided an infection with HRHPV if vaccinated with a bivalent or quadrivalent vaccine, and about a third of men would have potentially avoided an infection with HRHPV if vaccinated with a nonavalent vaccine (29.4%; 95% CI, 23.9–35.4; 75 of 255). The potential cancer protection from protection against HRHPV types in bivalent and quadrivalent vaccines did not change with increasing age (ptrend = 0.16), whereas for nonavalent vaccines, protection decreased with increasing age (ptrend = 0.03).

TABLE 4
TABLE 4:
Percentage of Men Who Could Potentially Benefit From Vaccination at Baseline and Proportion of Men Whose HRHPV Could Be Avoided if Actually Vaccinated, Stratified by Age Group

DISCUSSION

This is one of the first cohort studies in Australia to examine anal HPV in MSM living with HIV. To determine the potential benefit of HPV vaccines, it is important to determine the prevalence and incidence of HPV types within the targeted population because protection afforded by HPV vaccines is type specific.21,22 More than half of men did not have any vaccine-preventable HPV types at baseline, and virtually all men did not have all vaccine-preventable HPV types, so would potentially derive some cancer protection from HPV vaccination. In particular, 23% to 48% of men became positive to at least 1 nonavalent vaccine HPV type within 2 years (Table 4). The incidence and clearance rates we reported in this study are similar to studies of MSM living with HIV from Canada and Spain.7,8 These rates are also similar to young women entering sexual activity,23 the group that is the focus of many HPV vaccination programs. So, despite a high background prevalence of HRHPV, this high incidence of HRHPV suggests that a significant number of MSM living with HIV may potentially benefit from HPV vaccination.

Most studies of anal HPV have reported anal HPV at 1 timepoint,1,6,24 and less is understood about HPV type-specific incidence, persistence, and clearance in MSM living with HIV. Anal HRHPV, particularly HPV 16, is the most common cause of anal cancer.25 We found that two thirds of men with HPV 16 had persistent infection 2 years later, with the lowest rate of clearance of all HRHPV, that is, 16.7 per 100 person-years. This is consistent with 2 other cohort studies of MSM living with HIV. In a Canadian study, HPV 16 had a mean persistence of 3 years, with a clearance rate of 14.6 per 100 person-years.7 Similarly, for Spanish MSM living with HIV, HPV16 also had a low clearance rate (ie, 18.8 per 100 person-years).8 This is concerning because persistent HPV16 is associated with increased anal cancer susceptibility in MSM living with HIV1,3,4 and underscores the importance for vaccination as a primary prevention measure to reduce incident HPV 16 infections.

If men had been vaccinated at baseline and the vaccine had 100% efficacy against incident infection, then a significant proportion of men would be protected against incident HPV infection. Whether vaccination in men provides benefit against incident anal cancer in those who are antibody-positive and DNA-negative is debatable but is plausible given the data in women demonstrating protection against CIN.26–29 We estimate that a substantial proportion of MSM living with HIV may not be exposed to all HPV vaccine-preventable types. This concurs with a Sydney study reporting that none of their MSM living with HIV had detection of more than 5 of the HPV vaccine-preventable types for the nonavalent vaccine.24 Currently, under most national HPV programs worldwide, there are no targeted HPV programs for MSM living with HIV, though studies confirm that HPV vaccines are safe to administer to those living with HIV.30 Recently, the United Kingdom started a targeted program for HPV vaccination to MSM, including those living with HIV, who are 45 years or younger.31

Our study should be read in light of some limitations. First, common with other HPV studies, we could not determine whether a man had previously cleared HPV vaccine types or distinguish between reactivation and new infection. Access to type-specific serology may help identify these men though seroconversion may be low,32 and therefore not a useful measure to identify men who may benefit from HPV vaccination. Because currently available HPV vaccines are not therapeutic vaccines, the likely benefit of vaccination may be overestimated if a man had previously cleared HPV vaccine types. This is consistent with a recent randomized controlled trial showing no significant benefit for quadrivalent HPV vaccination in older MSM.33 However, our study demonstrates that the nonavalent vaccine may still be beneficial for older MSM if a substantial proportion of men had not been exposed to all HRHPV vaccine-preventable types. Our study estimates are likely to be the upper bounds of benefit of vaccination for MSM living with HIV. Second, a longer follow-up period beyond 2 years and more frequent anal HPV swabs would provide more information about the natural history of anal HPV in MSM living with HIV. The clearance rates of HRHPV range from 44 to 130 per 1000 person-months9 so there is a potential for infections to have occurred and cleared between the 2 measurements, leading to an underestimate our incidence rate. Third, this study may not represent the broader population of MSM living with HIV in Australia as our sample was taken from clinical sites where men older than 35 years volunteered for the anal cancer screening study and may therefore perceive themselves as having a higher risk for HPV acquisition. Therefore, our findings may underestimate the likely benefit of HPV vaccination in the broader MSM living with HIV population. Future studies could explore the cost-effectiveness study of providing HPV vaccination to MSM living with HIV to account for the variable efficacy of vaccine weighed against cost of vaccination and prevention of HPV-related cancers.

Men who have sex with men living with HIV have a high prevalence and incidence of anal HRHPV. The majority of MSM living with HIV, including older men, may still potentially benefit from the nonavalent HPV vaccine if not previously infected with HPV vaccine types.

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