Background
HIV-seropositive women face high risk for infection with oncogenic human papillomavirus (oncHPV) types, abnormal Pap test results, and precancer, but cervical cancer risk is only modestly increased. Human papillomavirus (HPV)16 is highly oncogenic but only weakly associated with HIV status and immunosuppression, suggesting HPV16 may have a greater innate ability to evade host immune surveillance than other oncHPV types, which in turn should result in a greater relative increase in the prevalence of other oncHPV types among women with cervical precancer.
Objective
We sought to assess whether the underrepresentation of HPV16 among HIV-seropositive relative to HIV-seronegative women remains among those with cervical precancers.
Study Design
HIV-seropositive and HIV-seronegative women in the Women’s Interagency HIV Study were screened for cervical intraepithelial neoplasia (CIN) grade ≥3 (CIN3 + ). DNA from >40 HPV types was detected by polymerase chain reaction in cervicovaginal lavage specimens obtained at the visit at which CIN3 + was diagnosed.
Results
HPV16 was detected in 13 (62%) of 21 HIV-seronegative women with CIN3 + but only 44 (29%) of 154 HIV-seropositive women with CIN3 + ( P = .01). The lower prevalence of HPV16 in CIN3 + among HIV-seropositive women persisted after controlling for covariates (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08–0.78). The prevalence of other members of the HPV16-related alpha-9 oncHPV clade as a group was similar in HIV-infected and uninfected women with CIN3 + (OR, 1.02; 95% CI, 0.53–1.94). The prevalence of non-alpha-9 oncHPV types was increased in HIV-seropositive vs HIV-seronegative women with CIN3 + (OR, 3.9; 95% CI, 1.3–11.8).
Conclusion
The previously demonstrated increase in CIN3 + incidence among HIV-seropositive women is associated with lower HPV16 and higher non-alpha-9 oncHPV prevalence. This is consistent with prior reports that HIV has a weak effect on infection by HPV16 relative to other oncHPV and supports use of nonavalent HPV vaccine in HIV-seropositive women.
Introduction
Compared with HIV-seronegative women, HIV-seropositive women face dramatically increased risks of infection with human papillomaviruses (HPVs), including oncogenic HPV (oncHPV) types. They also have a higher risk of abnormal Pap test results and precancer. However, cervical cancer risk is only modestly increased by HIV infection, and the incidence of cancer after 10 years of follow-up in a US national cohort of HIV-seropositive women was not significantly higher than that in HIV-seronegative women or US women of similar age.
The reasons for this discrepancy are unclear. Screening may reduce cancer risk among women in study cohorts by eliminating precursors, but treatment of cervical precancers in HIV-seropositive women often fails to result in clearance. An additional possibility is that many of the abnormal Pap test findings and cervical dysplasias found in HIV-seropositive women may reflect HPV infections of moderate oncogenic potential, with relatively few related to the highly oncHPV16.
HPV16 accounts for more than half of invasive cervical cancers in the general population, as well as a marginally smaller percentage of precancers. HPV16 is also more common than many less oncHPV types in HIV-seronegative but not HIV-seropositive women. Using data from 2 large, independent cohort studies of HIV infection, we observed that the prevalence of HPV16 had the weakest association of any oncHPV type with HIV status and immunosuppression, as measured by CD4 count. Our group and others interpreted this relative independence of HPV16 infection from host immune status as evidence that HPV16 may have a greater innate ability to evade host immune surveillance than other oncHPV types. If correct, this innate immunoevasiveness might partly account for the high prevalence of HPV16 in the general population. Moreover, the observed modest increase in cervical cancer risk among HIV-seropositive women may be explained at least in part if HPV16, the major etiologic risk factor for cervical cancer, is less strongly released by HIV-related immunosuppression than less oncHPV types.
If HPV16 has a greater innate ability than other oncHPV types to avoid the effects of immune surveillance, then HIV-related immunosuppression should result in a greater relative increase in the prevalence of other oncHPV types among women with cervical precancer, and the prevalence of HPV16 positivity in precancers should be lower on a relative scale. On the other hand, if non-16 oncHPV types are more common in HIV-seropositive women but HPV16 remains the driver for most oncogenic events, then the prevalence of HPV16 in precancers found in HIV-seropositive women should remain high.
To distinguish between these possibilities, we set out to assess the distribution and relative prevalence of individual HPV types among HIV-seropositive and HIV-seronegative women with cervical precancer and to assess the impact of age and other risk factors on the HPV type distribution in these women.
Materials and Methods
The Women’s Interagency HIV Study (WIHS) is a US multicenter cohort study of health outcomes among HIV-seropositive women. WIHS also enrolled HIV-seronegative comparison women. Enrollment began on Oct. 3, 1994, at 6 study consortia and over time has enrolled 4068 women, including those enrolled during expansions from 2001 through 2002 and 2011 through 2012. The study was designed to ensure that the cohort reflected the evolving HIV epidemic in US women. At each site, human subjects committees reviewed and approved the study, and all participants gave written informed consent. Follow-up continues, but this analysis includes information on histologic outcomes through March 31, 2012.
Single-slide conventional Pap smears were obtained every 6 months using spatula and brush and were read according to the 1991 Bethesda System for cervicovaginal diagnosis, with high-grade results subdivided as consistent either with moderate or with severe dysplasia. Colposcopy was required by study protocol for any epithelial cytologic abnormality, including those read as atypical squamous cells of undetermined significance. HPV testing was performed for research only and was not used in clinical management. Biopsy results were interpreted at local sites and were not centrally reviewed. Abnormal results were categorized as cervical intraepithelial neoplasia (CIN) grade 1, 2, or 3; adenocarcinoma in situ; or cancer. Postcolposcopy histology results, such as those from loop excision or hysterectomy, were abstracted from medical records.
At each visit, cervicovaginal lavage was conducted with 10 mL of saline. Protocols for semiannual HPV testing have been described previously. Briefly, MY09/MY11 consensus primers polymerase chain reaction (PCR) amplification was followed by hybridization with consensus and HPV type-specific probes. Successful amplification of the β-globin gene during PCR was used to assess specimen adequacy; β-globin-negative specimens were excluded. Results were classified as defined by the International Association for Research on Cancer, including any oncHPV type (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), for any type, and negative for HPV.
Preliminary data analysis examined the similarities and differences in characteristics between HIV-seropositive and HIV-seronegative cases of histologic CIN grade ≥3 (CIN3 + ) at the time of diagnosis, using the t test to assess means, the Wilcoxon test for medians, or the Pearson χ 2 test for proportions, as well as the Mantel extension test to assess ordinal data. Multivariate logistic regression models were used to explore the relative prevalence of each HPV type, or oncHPV phylogenetic species, by exposure factors such as HIV serostatus. These logistic regression models employed generalized estimating equation models to address multiple HPV types per woman.
Materials and Methods
The Women’s Interagency HIV Study (WIHS) is a US multicenter cohort study of health outcomes among HIV-seropositive women. WIHS also enrolled HIV-seronegative comparison women. Enrollment began on Oct. 3, 1994, at 6 study consortia and over time has enrolled 4068 women, including those enrolled during expansions from 2001 through 2002 and 2011 through 2012. The study was designed to ensure that the cohort reflected the evolving HIV epidemic in US women. At each site, human subjects committees reviewed and approved the study, and all participants gave written informed consent. Follow-up continues, but this analysis includes information on histologic outcomes through March 31, 2012.
Single-slide conventional Pap smears were obtained every 6 months using spatula and brush and were read according to the 1991 Bethesda System for cervicovaginal diagnosis, with high-grade results subdivided as consistent either with moderate or with severe dysplasia. Colposcopy was required by study protocol for any epithelial cytologic abnormality, including those read as atypical squamous cells of undetermined significance. HPV testing was performed for research only and was not used in clinical management. Biopsy results were interpreted at local sites and were not centrally reviewed. Abnormal results were categorized as cervical intraepithelial neoplasia (CIN) grade 1, 2, or 3; adenocarcinoma in situ; or cancer. Postcolposcopy histology results, such as those from loop excision or hysterectomy, were abstracted from medical records.
At each visit, cervicovaginal lavage was conducted with 10 mL of saline. Protocols for semiannual HPV testing have been described previously. Briefly, MY09/MY11 consensus primers polymerase chain reaction (PCR) amplification was followed by hybridization with consensus and HPV type-specific probes. Successful amplification of the β-globin gene during PCR was used to assess specimen adequacy; β-globin-negative specimens were excluded. Results were classified as defined by the International Association for Research on Cancer, including any oncHPV type (types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68), for any type, and negative for HPV.
Preliminary data analysis examined the similarities and differences in characteristics between HIV-seropositive and HIV-seronegative cases of histologic CIN grade ≥3 (CIN3 + ) at the time of diagnosis, using the t test to assess means, the Wilcoxon test for medians, or the Pearson χ 2 test for proportions, as well as the Mantel extension test to assess ordinal data. Multivariate logistic regression models were used to explore the relative prevalence of each HPV type, or oncHPV phylogenetic species, by exposure factors such as HIV serostatus. These logistic regression models employed generalized estimating equation models to address multiple HPV types per woman.
Results
Of the 2791 HIV-seropositive and 975 HIV-seronegative women enrolled in WIHS, CIN3 + was found in 154 (5.5%) HIV-seropositive and 21 (2.2%) HIV-seronegative women across all visits. Two women (both HIV seropositive) had invasive cancer; one was associated with HPV16 and HPV84, the other with HPV72 and HPV73. Table 1 presents the demographic characteristics at the time of diagnosis of CIN3 + . HIV-seropositive women were older (mean age 39.5 years) than HIV-seronegative women (mean age 32.8 years, P = .0001). They also were enrolled earlier in the study and were more often current smokers.
| HIV – , N = 25 | HIV + , N = 166 | P value a | |
|---|---|---|---|
| N (%) | |||
| Age, y | .001 | ||
| <30 | 11 (44) | 20 (12) | |
| 30–34 | 6 (24) | 33 (20) | |
| 35–39 | 4 (16) | 42 (25) | |
| 40–44 | 1 (4) | 30 (18) | |
| ≥45 | 3 (12) | 41 (25) | |
| Race | .08 | ||
| White | 3 (12) | 16 (10) | |
| Hispanic | 3 (12) | 41 (25) | |
| Black | 16 (64) | 105 (63) | |
| Others | 3 (12) | 4 (2) | |
| Enrollment period | .01 | ||
| 1994 through 1995 | 12 (48) | 126 (76) | |
| 2001 through 2002 | 13 (52) | 39 (23) | |
| 2010 | 0 (0) | 1 (1) | |
| Smoking | .02 | ||
| Never smoked | 4 (16) | 35 (21) | |
| Former smoker | 9 (36) | 22 (13) | |
| Current smoker | 12 (48) | 107 (65) | |
| Lifetime no. of male sexual partners | .28 | ||
| <5 | 2 (8) | 29 (18) | |
| 5–9 | 10 (40) | 40 (24) | |
| 10–49 | 8 (32) | 49 (30) | |
| ≥50 | 5 (20) | 46 (28) | |
| No. of male sexual partners past 6 mo | .08 | ||
| 0 | 6 (24) | 56 (34) | |
| 1 | 13 (52) | 93 (57) | |
| 2 | 2 (8) | 7 (4) | |
| ≥3 | 4 (16) | 7 (4) | |
| CD4 + count, cells/cmm | |||
| >500 | 26 (16) | ||
| 200–500 | 71 (43) | ||
| <200 | 67 (41) | ||
| HIV viral load, copies/mL | |||
| ≤4000 | 76 (46) | ||
| 4001–20,000 | 24 (15) | ||
| 20,001–100,000 | 34 (21) | ||
| >100,000 | 30 (18) | ||
| AIDS history | |||
| No | 94 (57) | ||
| Yes | 72 (43) | ||
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