pap smears: post-hysterectomy in HIV positive women

A rather striking retrospective study was just published from 2 clinics in Texas, showing a high rate of vaginal intraepithelial neoplasia (VAIN) and vaginal cancer in HIV-infected women with no prior history of abnormal cytologic screening and who had a hysterectomy for conditions other than cervical dysplasia and cancer (see hiv pap posthysterect obgyn2016 in dropbox, or Smeltzer S. Obstet Gynecol 2016; 128: 52). details:

--68 providers, 4 of whom did regular pap screening, with 1827 HIV-positive women seen in 2015. Rate of pap testing was 47%
--238 women were seen between 2000-2015 with a  history of HIV, previous hysterectomy, and no previous abnormal Pap test results
--Median follow-up time for the Pap test was 16 years.
--results:
    --164 (69%) had normal Pap test results
    --12 (5%) had results showing atypical cells of undermined significance and human papillomavirus-positive
    --55 (23.1%) had results showing low-grade squamous intraepithelial lesion
    --7 (2.9%) had results showing high-grade squamous intraepithelial lesion.
    --of those who underwent biopsy for abnormal pap tests:
            --15 (28%) had normal results
            --23 (43%) had VAIN 1
            --9 (16%) had VAIN 2
            --7 (13%) had VAIN 3
            --No patients had invasive vaginal cancer.
    --No demographic risk factor was associated with the abnormal Pap test results after hysterectomy (race, smoking history, alcohol history, illegal drug use). Also no association with a specific indication for the hysterectomy (fibroids vs pelvic pain vs bleeding). The story was mixed on HIV-related risk factor (though overall there was not much difference in CD4 or viral load between those with normal vs abnormal paps, within 6 months of the pap abnormalities there was a significant deterioration: median CD4 was 573 vs 364, and viral load was 248 vs 400, all values with p<0.001)
    --Older patients and higher viral load significantly increased the risk of development of an abnormal Pap test result. For example, the patients with viral load values greater than 400 had approximately two times the risk of developing an abnormal Pap test result than those lower than 400; the adjusted hazard ratio of 2.1 (95% CI 1.2–3.5). In terms of age: 30-38yo HR 2.2, 38-44yo HR 3.8, >44yo HR 6.3
    --No difference in time to abnormal Pap test result was noted with antiretroviral use, or by CD4.


commentary:
--no guidelines suggest regular pap screening for women with a hysterectomy, unless the hysterectomy was done for cancer or precancerous lesions
    ​--USPSTF, Am Cancer Society, ACOG, etc are against routine screening in these women overall:  "The USPSTF recommends against screening for cervical cancer in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (cervical intraepithelial neoplasia [CIN] grade 2 or 3) or cervical cancer", giving it a "D" recommendation
        --however, I should add that old studies did find a non-zero but low risk of vaginal abnormalities in women in the general population getting a pap smear post-hysterectomy for benign causes (see Pearce KF. N Engl J Med 1996; 335: 1559, which noted that of 9610 vaginal smears, atypical squamous cells of undetermined significance (ASCUS) occurred in 52 (0.5%); low-grade squamous intraepithelial lesion in 44 (0.5%); high-grade squamous intraepithelial lesion in 6 (0.1%); and squamous-cell carcinoma in 2 (0.02%). In 5 women, biopsies revealed vaginal intraepithelial neoplasia type I or II; there were no biopsy-proved cases of vaginal cancer. The probability of an abnormal Pap smear in this group of women was 1.1 percent, and the positive predictive value of the Pap test for detecting vaginal cancer was 0. Mean time to get potentially significant intraepithelial lesions was 19 yrs. Because of the age of this study, there was no information about HIV or HPV status.
    --there are very limited data and no clear recommendations on pap testing in hiv-positive women having a hysterectomy for benign reasons.
--there are several unanswered questions (which really should be studied).
    --this Texas study was a retrospective analysis with limited data collected and there are no data I've seen on the effect of interventions on changing actual clinical outcomes in abnormalities picked up by routine screening
    --we know that HPV infection tends to persist in HIV-positive men and women, with attendant increased risk of anal and cervical cancers. it would be great if there were prospective data looking at HPV status and vaginal paps in women.​​ In the above study, the ASCUS findings were associated with HPV. My guess is that HPV is the culprit and that it seems reasonable to consider HPV and/or pap screening in women with HPV infection at the time of hysterectomy and later if at risk for getting an HPV infection.  But this should be studied. And it is really important that  we pursue HPV vaccination rigorously in young women (and men).

        --since there was a deterioration of HIV markers (CD4 and viral load) within 6 months of the abnormal pap, perhaps should we be doing selective paps on those with HIV deterioration, or at certain levels of these counts. Again, it would be good to know prospectively if changes in HIV markers consistently preceded vaginal cytology abnormalities.
        --this study was done in a single population/demographic area. is it generalizable?
        ​--is there any relationship  between numbers of sexual partners, partners infected with HIV, etc and the development of VAIN?
--so, this study does throw a bit of a wrench into conventional wisdom. it is pretty clear that there is more of a risk for vaginal cytologic abnormalities in women with HIV who get a hysterectomy for benign reasons than we had thought, and that recommendations be reconsidered given the relatively benign test (pap), and further work-up (biopsy). to me, it is not unreasonable to assume that for a woman with significant abnormalities on vaginal biopsy and with pathological deterioration on observation/local therapy, that definitive therapy be considered. 

--but, at this point, it does seem reasonable to do vaginal pap smears on women with HIV and hysterectomy for benign reasons. unclear what interval. but it seems from the data that these are not very aggressive or rapidly progressive evolution from VAIN to cancer, so likely that they could be done every several years