Pap smear outcomes in elderly women living with HIV and HIV-negative matched controls

Abstract

Objectives

To describe risk factors/incidence of abnormal cervical/vaginal cytology/histology and cancer among women living with human immunodeficiency virus (WLHIV) ≥65 years compared to HIV-negative matched controls

Study Design

Retrospective cohort of patients who underwent Pap screening at the University of Maryland 01/2003-04/2019.

Results

WLHIV and HIV-negative controls (n = 70 each) underwent 140/151 Pap tests, respectively. Among WLHIV, 29% exhibited abnormal results and were less likely than HIV-negative women with normal Paps to have had serially negative Pap tests prior to age 65 (p = .03). In both groups, 1.4% developed cervical cancer. Abnormal Paps were more frequent in WLHIV than in HIV-negative women (31% vs 10%, p < .0001, RR:3.2, 95%CI1.9–5.4) as was HRHPV (high-risk human papillomavirus) status (43% vs 19%, p = .0233, RR:2.3, 95%CI1.2–4.6). The RR for an abnormal Pap was 2.6 (95% CI:1.1–4.2) for VL >1000 copies/mL and 0.4 (95% CI:0.2–0.7) for CD4 count of >200 cells/μL. No individual with an initially normal Pap experienced an abnormal result over a mean of 42.5 and 43.5 months in the HIV-positive and HIV-negative groups, respectively.

Conclusions

HIV status was associated with a higher rate of abnormal Pap/HRHPV; however, no significant difference in cervical/vaginal cancer. Elevated VL/low CD4 count were associated with greater risk for an abnormal Pap.

Keywords

HIV pap screening elderly

Introduction

There are an estimated 36.9 million individuals worldwide living with human immunodeficiency virus (HIV). In developing nations, 10% are 50 years or older. In developed countries such as the United States and territories, nearly half of all patients with HIV are ≥50 years, and one in six new diagnoses occur in this age group.¹ As people living with HIV with a positive CD4 response to anti-retroviral therapy (ART) have no compromise in life expectancy,² the optimal care of an aging HIV-positive population is becoming an increasingly important area of study.

Women living with HIV (WHLIV) face a greater risk of cervical squamous intraepithelial lesions (SILs)^3–6 and cervical cancer^5,7,8 compared to HIV-negative counterparts, however, implementation of appropriate cervical cancer screening may confer similar incidences of invasive cervical cancer between WLHIV and HIV-negative women, at least among the non-elderly.⁹ In the general population, current American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines suggest that screening may cease at 65 years if preceded by two negative co-tests (cytology in combination with high-risk human papilloma virus [HRHPV]) or three negative cytology tests within the past 10 years, the most recent test within the past 5 years, and no cervical intraepithelial neoplasia (CIN) two or more serious lesions within the past 20 years¹⁰ In contrast, the U.S. Department of Health and Human Services (DHHS) and the American College of Obstetricians and Gynecologists (ACOG) endorse continuation of cervical cancer screening in WLHIV indefinitely beyond age 65.^11,12 The most recent position paper of the European Society of Gynaecologic Oncology and European Federation of Colposcopy does not comment on this population.¹³ Notably, evidence to substantiate this guidance remains limited to expert opinion, and customized management based on known risk modifiers, such as HRHPV co-infection,^3,5,14 smoking status,¹⁴ CD4 count,^{3,5,8,15–18} viral load,¹⁸ and ART,^5,16,18 would have great potential to further inform screening guidelines in older women with HIV.

This retrospective cohort study was designed to assess the incidence of cervical/vaginal cancers as well as abnormal Pap results in WLHIV age 65 and older, compared to a matched control group of HIV-negative women. We also sought to identify risk factors associated with abnormal Pap results in these cohorts to assist in future algorithms for risk stratification.

Methods

This protocol was approved by the Institutional Review Board (HP-00082189). We retrospectively identified WLHIV and matched HIV-negative controls ≥65 years who underwent Pap screening at the University of Maryland Medical System between January 2003–April 2019. Women with gynecologic malignancy prior to age 65 were excluded. Additional exclusion criteria were unknown smoking status and immunosuppression due to transplant. Documented HIV-positive serostatus defined the study group, while confirmation of HIV-negative serostatus was not necessary for the control group. For the initial analysis, only the earliest Pap test meeting criteria was used, though results were subsequently reanalyzed using all available Pap smear results at age ≥65 years.

Controls were matched based on age, year resulted, and smoking status (ever, former, current)¹⁴ at the time of collection. Four individuals were matched to Pap tests collected during a different year. Additionally, four women were matched to former, instead of current, smokers based on available matches. To attempt to balance this, four other women were matched to current, rather than former, smokers.

Characteristics (Table 1) were extracted from the electronic medical record. In women with prior hysterectomy, vaginal cytology results were recorded. Presence of an abnormal Pap test prior to age 65 was defined by history. All patients classified as having serially negative Pap tests were restricted to those with confirmed cytology. Pap results were classified as abnormal if colposcopy was indicated based on the ASCCP guidelines published at that point in time,^19–21 to account for changes in guidance that occurred in 2012.

Table 1.

Characteristics of women living with women living with HIV and HIV-negative controls.

Characteristic	All Women			WLHIV
Characteristic	WLHIV (n = 70)	HIV-negative (n = 70)	p	Normal Pap (n = 50)	Abnormal Pap (n = 20)	p
Age (y)	66 (65–68)	66 (65–68)	Controlled	66 (65–68)	66 (65–67.8)	.760
Year of Pap collection	2016 (2012–2017)	2016 (2012–2017)	Controlled	2016 (2012–2017)	2016 ( 2010–2017)	.951
Race/ethnicity
Non-Hispanic Black	68 (97.1)	36 (51.4)	<.0001	49 (98.0)	19 (95.0)	.493
Non-Hispanic White	1 (1.4)	32 (45.7)		0 (0)	1 (5.0)
Hispanic	0 (0)	0 (0)		0 (0)	0 (0)
Asian	0 (0)	1 (1.4)		0 (0)	0 (0)
Native American	0 (0)	0 (0)		0 (0)	0 (0)
Other	1 (1.4)	0 (0)		1 (2.0)	0 (0)
Unknown	0 (0)	1 (1.4)		0 (0)	0 (0)
Primary insurance
Uninsured	0 (0)	0 (0)	.0015	0 (0)	0 (0)	.343
Medicare/Medicaid	64 (91.4)	52 (74.3)		45 (90.0)	19 (95.0)
Ryan White Grant	2 (2.9)	0 (0)		2 (4.0)	0 (0)
Private	3 (4.3)	16 (22.9)		3 (6.0)	0 (0)
Unknown	1 (1.4)	2 (2.9)		0 (0)	1 (5.0)
Parity^a	3 (2–4.8)	2 (1–3)	.0062	2 (2–4)	3 (2–7)	.339
BMI (kg/m²)
<18.5	5 (7.1)	0 (0)	.0052	2 (4.0)	3 (15.0)	.0764
18.5–24.9	21 (30.0)	10 (14.3)		12 (24.0)	9 (45.0)
25.0–29.9	17 (24.3)	19 (27.1)		15 (30.0)	2 (10.0)
30.0–39.9	22 (31.4)	25 (35.7)		18 (36.0)	4 (20.0)
40.0+	2 (2.9)	11 (15.7)		1 (2.0)	1 (5.0)
Unknown	3 (4.3)	5 (7.1)		2 (4.0)	1 (5.0)
Tobacco use
Never	18 (25.7)	18 (25.7)	Controlled	14 (28.0)	4 (20.0)	.113
Former	24 (34.3)	24 (34.3)		20 (40.0)	4 (20.0)
Current	28 (40.0)	28 (40.0)		16 (32.0)	12 (60.0)
Alcohol use
Never	50 (71.4)	66 (94.3)	.0006	40 (80.0)	10 (50.0)	.0129
Former	15 (21.4)	4 (5.7)		9 (18.0)	6 (30.0)
Current	5 (7.1)	0 (0)		1 (2.0)	4 (20.0)
Drug use
Never	41 (58.6)	67 (95.7)	<.0001	32 (64.0)	9 (45.0)	.152
Former	15 (21.4)	2 (2.9)		11 (22.0)	4 (20.0)
Current	14 (20.0)	1 (1.4)		7 (14.0)	7 (35.0)
Hysterectomy for benign indication	32 (45.7)	13 (18.6)	.001	24 (48.0)	8 (40.0)	.603
History of abnormal Pap at age <65
No	23 (32.9)	30 (42.9)	.0024	19 (38.0)	4 (20.0)	.292
Yes	35 (50.0)	16 (22.9)		22 (44.0)	13 (65.0)
Unknown	12 (17.1)	24 (34.3)		9 (18.0)	3 (15.0)
Serially negative Pap tests^b	1 (0–3.5)	2 (1–5)	.0281	1 (1–5)	1 (0–1)	.0311

HIV: human immunodeficiency virus; BMI: body mass index; WLIHV: women living with HIV. Data are median (interquartile range), n (%), or mean ± SD unless otherwise specified.

Abnormal Pap result defined as one for which colposcopy was indicated.

Fisher exact test was used for categorical variables; Mann-Whitney or unpaired t test were used for continuous data.

^aData unknown in 6 WLHIV (5 with normal Pap, 1 with abnormal Pap) and 10 HIV-negative women.

^bData unknown in 21 WLHIV (16 with normal Pap, 5 with abnormal Pap) and 24 HIV-negative women.

Our outcomes of interest included cytology, HRHPV status, colposcopy performed when indicated, colposcopic impression, development of abnormal cytology over time, and development of biopsy-confirmed cervical/vaginal cancer.

Descriptive statistics were used. For analyses between groups, we used the Mann-Whitney or unpaired t-test for continuous variables and Fisher’s exact test for categorical variables. Unknown variables were included in analyses unless otherwise specified. Statistical analyses were performed using GraphPad Prism version 8.1.1 (San Diego, CA) and SAS© v.9.04.01M3P062415 (SAS Institute Inc, Cary, NC). A p value of <.05 was considered significant.

Results

Figure 1 depicts a flowchart of the study participants. A total of 140 women were included. Demographic characteristics between the study and control groups were significantly different across every variable (Table 1). Rate of previous hysterectomy was significantly higher in the HIV-positive compared with the HIV-negative group (45.7% versus 18.6%, respectively, p = .001), as was the number with abnormal Pap tests prior to age 65 years (50.0% versus 22.9%, respectively, p = .0024). The number of serially negative Pap results immediately preceding age 65 was lower in WLHIV (1 vs 2, respectively, p = .0281). No more than 30% in the HIV-negative and 20% in the HIV-positive groups had prior screening documented. Insurance status differed significantly, with greater access to private insurance in the HIV-negative cohort (22.9% versus 4.3%, p = .0015).

Figure 1.

Flowchart of study population and matched controls. WLHIV: women living with HIV.

Among WLHIV, an abnormal Pap result was associated with alcohol use and number of serially negative Pap results (Table 1-right). The study group more commonly carried a diagnosis of mental health disorder, dementia, hepatitis B, or hepatitis C (p < .0001, p = .0088, p < .0001, and p < .0001, respectively). There were no significant differences in the diagnosis of diabetes, cardiovascular disease, dyslipidemia, syphilis, genital herpes simplex virus, and non-gynecological cancer (p = .854, p = .324, p = .711, p = .116, p = .0967, and p = .515, respectively).

A total of 1.4% in each group developed cervical cancer (Table 2-top) and no individual developed vaginal cancer. Neither of the two individuals who developed cervical cancer in our cohort had a history of abnormal Pap tests; however, the HIV-negative individual had been absent from gynecologic care for 15 years and the HIV-positive individual’s previous gynecological visit or Pap test was not documented. Both presented with gynecological symptoms. They were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB and IA squamous cell carcinoma, respectively. Both patients are currently alive without disease.

Table 2.

Top: Outcomes grouped by first Pap (left) or all Pap results (right). Bottom: Cytologic results across the study group and matched controls.

Outcome	First Pap				All Paps
Outcome	WLHIV (n = 70)	HIV-negative (n = 70)	RR (95% CI)	p	WLHIV (n = 140)	HIV-negative (n = 151)	RR (95% CI)	p
Cervical cancer	1/70 (1.4)	1/70 (1.4)	1.0 (0.1–9.5)	1.000	––	––	––	––
Vaginal cancer	0/70 (0)	0/70 (0)	––	1.000	––	––	––	––
Abnormal Pap result	20/70 (28.6)	5/70 (7.1)	4.0 (1.7–9.9)	.0016	44/140 (31.4)	15/151 (9.9)	3.2 (1.9–5.4)	<.0001
High-risk HPV positive	13/29 (44.8)	3/23 (13.0)	3.4 (1.2–10.5)	.0172	21/49 (42.9)	8/42 (19.0)	2.3 (1.2–4.6)	.0233
Colposcopy performed when indicated	9/20 (45.0)	4/5 (80.0)	0.6 (0.3–1.3)	.322	18/45 (40.0)	9/15 (60.0)	0.7 (0.4–1.2)	.235
Colposcopy impression
Inadequate	1/9 (11.1)	0/4 (0)	––	.790	2/18 (11.1)	0/9 (0)	––	.0056
Negative	4/9 (44.4)	2/4 (50)			12/18 (66.7)	2/9 (22.2)
LSIL	2/9 (22.2)	1/4 (25)			2/18 (11.1)	6/9 (66.7)
HSIL	2/9 (22.2)	0/4 (0)			2/18 (11.1)	0/9 (0)
Suspicious for SCC	0/9 (0)	1/4 (25)			0/18 (0)	1/9 (11.1)

HIV: human immunodeficiency virus; RR: relative risk; HPV: human papilloma virus; LSIL: low-grade squamous intraepithelial lesions; HSIL: high-grade squamous intraepithelial lesions; SCC: squamous cell carcinoma; WLHIV: women living with HIV.

Data are n/N (%) unless otherwise specified.

Abnormal Pap result defined as colposcopy indicated.

Fisher exact test was used for categorical variables (p<0.05).

Cytology	First Pap		All Paps
HPV result	WLHIV (n = 70)	HIV-negative (n = 70)	WLHIV (n = 140)	HIV-negative (n = 151)
NILM	52 (74.3)	64 (91.4)	100 (71.4)	130 (86.1)
Negative	14 (20.0)	18 (25.7)	21 (15.0)	28 (18.5)
Positive	5 (7.1)	1 (1.4)	10 (7.1)	1 (0.66)
Unknown	33 (47.1)	45 (64.3)	69 (49.3)	101 (66.9)
ASC-US	9 (12.9)	4 (5.7)	20 (14.3)	10 (6.6)
Negative	2 (2.9)	2 (2.9)	7 (5.0)	6 (4.0)
Positive	4 (5.7)	2 (2.9)	6 (4.3)	3 (2.0)
Unknown	3 (4.3)	0 (0)	7 (5.0)	1 (0.66)
ASC-H	1 (1.4)	0 (0)	1 (0.71)	0 (0)
LSIL	6 (8.6)	1 (1.4)	15 (10.7)	10 (6.6)
HSIL	2 (2.9)	0 (0)	3 (2.1)	0 (0)
Suspicious for SCC	0 (0)	1 (1.4)	1 (0.71)	1 (0.66)

HIV: human immunodeficiency virus; HPV: human papilloma virus; ASC-US: atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions; LSIL: low-grade squamous intraepithelial lesions; HSIL: high-grade squamous intraepithelial lesions; SCC: squamous cell carcinoma; WLHIV: women living with HIV.

Data are n (%) unless otherwise specified.

The risk of an abnormal Pap result was significantly greater in women with HIV (RR 4.0, 95% CI 1.7–9.9, p = .0016), as was positive HRHPV result (RR 3.4, 95% CI 1.2–10.5, p = .0172). When data were re-analyzed to account for all Pap results (n = 140 in the HIV-positive and n = 151 in the HIV-negative groups) rather than only the initial Pap at age 65 or older (Table 2-top), the prevalence of abnormal Pap results and HRHPV remained significantly elevated in the study group (RR 3.2, 95% CI 1.9–5.4, p < .0001; RR 2.3, 95% CI 1.2–4.6, p = .0233, respectively). Appropriate performance of colposcopy when indicated was not significantly different between groups. Colposcopic impression became statistically significant only when all Pap results were included.

The HIV-negative group had significantly more low-grade squamous intraepithelial lesions (LSIL) results, whereas the HIV-positive group had significantly more negative for intraepithelial lesion or malignancy (NILM) results (p = .0056). Table 2-bottom shows the breakdown of all cytology results.

HIV disease characteristics are displayed in Table 3-top. Viral load, CD4 count, and ART use in WLHIV was not significantly different between those with an initial normal versus abnormal Pap result (Table 3-bottom). When data were re-analyzed by including all available Pap tests, rather than only the initial Pap test, viral load and CD4 count became significant. The relative risk of developing an abnormal Pap test with a viral load of 1000 copies/mL or greater was 2.6 (95% CI 1.1–4.2, p = .0493) or with a CD4 count of 200 cells/μL or greater was 0.4 (CI 0.2–0.7, p = .0040).

Table 3.

Top: HIV disease characteristics. Bottom: High viral load and low CD4 count were predictors of abnormal Pap results among older women living with HIV.

Outcome	Normal Pap (n = 50)	Abnormal Pap (n = 20)
Age at HIV diagnosis^a	54.0 ± 8.1	53.7 ± 8.8
Met CDC-defined criteria for AIDS	25/49 (51.0)	9/19 (47.4)
Risk factor for HIV acquisition
Sex	27 (54.0)	11 (55.0)
IV drug use	4 (8.0)	4 (20.0)
Blood products	0 (0)	1 (5.0)
Occupational exposure	2 (4.0)	2 (10.0)
Multiple	9 (18.0)	2 (10.0)
Unknown	8 (16.0)	0 (0)

HIV: human immunodeficiency virus; CDC: Centers for Disease Control; IV: intravenous.

Data are mean ± SD or n/N (%) unless otherwise specified.

Abnormal Pap result defined as colposcopy indicated.

^aData unknown in 3 with normal Pap and 1 with abnormal Pap.

Outcome	First Pap		RR (95% CI)	p
Outcome	Normal Pap (n = 50)	Abnormal Pap (n = 20)	RR (95% CI)	p
Viral load (copies/mL)
<1000	46/48 (95.8)	16/19 (84.2)	2.3 (0.8–4.4)	.134
1000+	2/48 (4.2)	3/19 (15.8)	2.3 (0.8–4.4)	.134
CD4 count (cells/μL)
<200	3/48 (6.3)	4/19 (21.1)	0.4 (0.2–1.1)	.0937
200+	45/48 (93.8)	15/19 (78.9)	0.4 (0.2–1.1)	.0937
Prescribed ART	43/48 (89.6)	16/19 (84.2)	0.7 (0.3–2.1)	.678

HIV: human immunodeficiency virus; RR: relative risk; ART: anti-retroviral therapy.

Data are n/N (%) unless otherwise specified.

Abnormal Pap result defined as colposcopy indicated.

Fisher exact test was used for categorical variable.

Mann-Whitney test was used when analyzing continuous data.

p-values in boldface are statistically significant (<.05).

In this cohort, 26 WLHIV and 32 women without HIV had >1 Pap test collected at age 65 or older. Importantly, of those with a normal initial Pap, none went on to experience an abnormal result (Table 4-top) over a mean of 42.5 and 43.5 months in the study and control groups, respectively, suggesting that current ASCCP screening intervals²¹ among the younger general population may be applicable to older WLHIV. Although not significant, WLHIV with an initial abnormal Pap test were less likely to revert to normal (33.3% versus 66.7%, p = .525). The mean time to next normal Pap was 23.5 months in those with HIV. The small sample size precluded a meaningful assessment in the HIV-negative group. The specific cytology results of the first and last Pap tests for the WLHIV are displayed in Table 4-bottom.

Table 4.

Top: Cytologic trends over time older women living with HIV and HIV-negative women. Bottom: Change in cytologic results among older women living with HIV.

Trend	WLHIV (n = 26)	HIV-negative (n = 32)	p
Initial Pap normal
Remained normal	14/14 (100)	29/29 (100)	1.000
Became abnormal	0/14 (0)	0/29 (0)	1.000
Initial Pap abnormal
Returned to normal	4/12 (33.3)	2/3 (66.7)	.525
Remained abnormal	8/12 (66.7)	1/3 (33.3)	.525

HIV: human immunodeficiency virus; WLHIV: women living with HIV.

Data are n/N (%) unless otherwise specified.

Abnormal Pap result defined as colposcopy indicated.

Fisher exact test was used for categorical variables.

First result	Last result
First result	NILM	ASC-US	ASC-H	LSIL	HSIL	Suspicious for SCC	Total
NILM	14/14 (100)	––	––	––	––	––	14
ASC-US	4/7 (57.1)	2/7 (28.6)	––	1/7 (14.3)	––	––	7
ASC-H	1/1 (100)	––	––	––	––	––	1
LSIL	1/3 (33.3)	2/3 (66.7)	––	––	––	––	3
HSIL	––	––	––	––	––	1/1 (100)	1
Suspicious for SCC	––	––	––	––	––	––	0

HIV: human immunodeficiency virus; NILM: negative for intraepithelial lesions or malignancy; ASC-US: atypical squamous cells of undetermined significance; ASC-H: atypical squamous cells, cannot exclude high-grade squamous intraepithelial lesions; LSIL: low-grade squamous intraepithelial lesions; HSIL: high-grade squamous intraepithelial lesions; SCC: squamous cell carcinoma; WLHIV: Women living with HIV.

Data are n/N (%) unless otherwise specified.

Discussion

In 2021, there were an estimated 14,480 cases and 8180 cases of vaginal cancer diagnosed in the United States.²² In 2020, worldwide there were 604,127 cases and 341,831 deaths from cervical cancer.²³ Globally, 5% of all cervical cancer cases are attributable to HIV infection and the proportion of women living with HIV among patients with cervical cancer ranges from <5% in 122 countries to ≥40% in nine countries. Some estimates suggest that 25% of cases in developed nations will be diagnosed in women ≥65 years, and the elderly are more likely to be diagnosed at stage II or higher.²⁴ Residual cumulative cancer incidence is as high as 60/100,000 by age 80 years in women exiting screening with three negative cytologic results.²⁵ After correcting for hysterectomy status, Rositch et al.²⁶ demonstrated that women age 65–69 years actually have the greatest incidence of invasive cervical cancer. Another case series found that 50% of their population who developed cervical cancer at age 65 years or older had appropriately discontinued screening.²⁷ Those with/without sufficient screening had similar rates of abnormal Pap results preceding age 65 years. Some therefore argue that continued screening beyond 65 years old should be re-examined in certain subsets of an HIV-negative population.^{28–30,31,32}

To our knowledge, this is the first study to describe the pattern of cytologic results and subsequent cancer diagnosis in WLHIV ≥65 in relationship to HIV-negative matched controls. We found that while HIV-positivity was associated with a higher rate of abnormal cytology and presence of HRHPV, this did not necessarily translate into a significant difference in risk of subsequent cancer diagnosis. While this may represent limitations of a small sample size and retrospective design, this may also affirm that WLHIV who participate in appropriate surveillance schemes enjoy a low risk of developing cervical or vaginal cancers. The high rate of abnormal cytology and HRHPV supports a need for continued screening in this population.

Since demographic variables were significantly different between the study and control groups, attributing our results merely to HIV status is not necessarily appropriate. Importantly, our data continue to highlight the racial disparities associated with HIV diagnosis, as 97% of women identified as non-Hispanic black in the HIV-positive group compared to only 51% in the HIV-negative group. In the United States, African-Americans suffer from the highest prevalence of HIV and associated mortality rates.³³ The only demographic factors that remained significant when comparing WLHIV with normal versus abnormal Pap results included alcohol use and number of serially negative Pap smears. Consistent with the findings of others, alcohol use has recently been associated with development of CIN1,³⁴ progression to cervical cancer,³⁵ and reduced pelvic control in women undergoing radiation for cervical cancer,³⁶ possibly due to changes in immune function and other carcinogenic metabolic effects.

Per ACOG guidelines, total hysterectomy is an indication to discontinue Pap smears except in those with a history CIN2 or a more severe lesion within the preceding 20 years³⁷ In our patients, higher rates of hysterectomy in the HIV-positive group were not protective against subsequent abnormal cytology. Our findings are concordant with another study that assessed post-hysterectomy vaginal cytology in WLHIV with no prior abnormal Pap tests and demonstrated that 31% developed abnormal results.³⁸ Nevertheless, we witnessed no cases of vaginal cancer in our series, possibly due to identification and treatment of pre-malignant lesions and its inherent rarity.

Our findings along with those of others suggests that risk stratification may optimize screening practices. Our cohort of WLHIV age ≥65 years demonstrated a higher rate of NILM compared to Aserlind et al.³⁹ In contrast to our results, in which no woman with an initial NILM Pap result experienced an abnormal result thereafter, 35% and 9% of their cohort developed ASC-US and LSIL, respectively. Important differences in their population include a 20% uninsured status and 79% CDC-defined AIDS. Due to their low rate of high-grade lesions, the authors expressed reservation on sustaining current screening practices.

Our longitudinal findings may indicate that longer intervals between Pap tests in elderly lower risk WLHIV could be reasonable. Current recommendations for younger women with HIV permit spacing to a 3 years screening period if the patient has three consecutive negative cytology results or one negative co-test.¹¹ Robins et al.⁴⁰ confirm the appropriateness of this algorithm and assert that CD4 count may further direct management. In a study of women with HIV by Harris et al.,⁴¹ a negative HPV result and a CD4 count of more than 500 cells/μL had a comparable cumulative incidence of dysplasia over 3 years to HIV-negative women. Aho et at.¹⁸ suggest that low risk WLHIV may be eligible for similar screening practices as HIV-negative women.

By stratifying by CD4 count and viral load, we successfully identified WLHIV at greater risk for abnormal Pap results. Similarly, Stewart et al.⁴² identified CD4 count <200 at time of HIV diagnosis or Pap in women ≥65 years to be predictive of an abnormal result. Given these findings, incorporating CD4 count and viral load into future screening guidelines for older women seems reasonable to explore to identify a sub-population of WLHIV who may be candidates for less stringent screening. Also considering the number of serially negative Pap tests in screening decisions may be appropriate.

A major and unique strength of this study is comparison with a matched control group. Additionally, we defined abnormal results based on guidelines available at the time of Pap collection and incorporated prior results into the designation, mirroring clinical practice. The generalizability of this study may be limited, as there was a lack of racial and ethnic diversity with 97% of the WLHIV self-identified as black. Our cohort also had relatively well-controlled HIV as well as access to care evident in the absence of uninsured individuals. Other limitations include the small sample size and lack of confirmation of colposcopic impression by biopsy. As with all retrospective study designs, missing data and unmeasured confounders complicate conclusions. Notably, women with history of a hysterectomy or abnormal Pap test were not excluded. We also did not examine the role of chronicity of HIV infection, which might further contribute to biologic aging and alter the immune milieu of the lower genital tract due to the interplay of HIV, co-infections, and long-term anti-retroviral use, among other incompletely elucidated factors.

In summary, we found increased risk for abnormal Pap tests in elderly WLHIV compared with HIV-negative matched controls. Rates of cervical cancer were the same and there were no cases of vaginal cancer. A CD4 count less than 200 cells/μL or a viral load of ≥1000 copies/mL significantly increased the risk for an abnormal Pap result. Future studies in broader settings with a larger population conducted as prospective clinical trial would further validate screening recommendations prompted by our initial observations in this population.

Footnotes

Author Notes

This work had been presented as a poster at the Mid-Atlantic Gynecologic Oncology Society 2019 Annual Meeting, Charlotte, NC, Oct 24–26, 2019; it had also been accepted for poster presentation at Society of Gynecologic Oncology Annual Meeting, Toronto, Mar 28–31, 2020.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Dana M Roque

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