Cervical cancer remains an important disease burden for HIV-infected women in the era of combination antiretroviral therapy (cART). These women bear an increased human papillomavirus (HPV) prevalence and reduced clearance due to immune impairment, leading to reactivation of latent HPV infections and induced HPV-related lesions.1–5 This association is more pronounced in the context of advanced immunodeficiency6–10 with a low cumulative incidence of intraepithelial lesions among HIV-infected women with CD4+ counts above 500cells/mm3 and HPV-negative at baseline.2 A systematic review found a slightly higher risk for cervical cancer after the introduction of combined antiretroviral therapy (cART).11 The increased survival associated with cART use has been linked to a higher risk of cancer, including those linked to HPV.11,12

Recommendations for cervical screening in HIV-infected women diverge. The Centers for Disease Control and Prevention (CDC) recommendations include semiannual cervical screening with cytology in the first year after HIV diagnosis, followed by annual cytology.13 On the other hand, the World Health Organization recently recommended a three-year interval for HIV-infected women whose screening was negative.14 The American Society of Colposcopy and Cervical Pathology suggests similar management of abnormal cytology for HIV-infected and uninfected women, which includes the use of high-risk HPV (HRHPV) testing.15 Brazilian guidelines recommend cytology screening every 3 years after two negative annual results for HIV-uninfected women with ages 25–64 years, and annual screening for HIV-infected women with CD4+ count higher than 500cells/μL and every 6-months for lower counts.16 Although the American College of Obstetricians and Gynecologists have recommended high-risk HPV (HRHPV) cervical screening testing as a complement for cytology in HIV-infected women,17 this test is not included in the Brazilian cervical cancer screening recommendations for this population.16

HRHPV testing has been employed as a useful tool for cervical screening in HIV-uninfected women, but data on its role for the management of HIV-infected women is limited, especially in low and middle income settings. Data regarding this topic in Latin America are lacking. An economic analysis suggested that combining both cytology and HRHPV testing might be cost-effective for HIV-infected women in Brazil.18 In this manuscript, our aim was to evaluate the clinical usefulness of a single HRHPV as a screening test for cervical abnormalities among HIV-infected women in a Brazilian cohort.

In total, 1156 women enrolled the cohort from May 1996 to December 2012. For the present analysis, 723 women with a normal cytology at baseline were included. Four hundred and thirty-three women were excluded: 299 and seven for having an abnormal or missing baseline cytology, respectively, 13 for having missing baseline HRHPV testing, 35 due to previous hysterectomy or cervical treatment, three for prior HPV vaccination (3), and 76 for not having any follow-up information.

For ‘any SIL’ and ‘HSIL+’ outcomes, a total of 723 women were followed for 3227 and 4218 person-years (PY), with a median follow-up of 3.5 (IQR, 1.3–6.5) and 5.3 years (IQR, 2.6–8.8), respectively. Among the 723 women, 144 and 237 were censored respectively for ‘any SIL’ and ‘HSIL+’ outcomes, out of which: 38 (26.4%) and 74 (31.2%) died, 20 (9.2%) and 36 (15.2%) had cervical treatment or hysterectomy, 7 (3.2%) and 8 (3.4%) were vaccinated for HPV, and 79 (54.9%) and 119 (50.2%) were lost to follow-up.

Any SIL incidence rate and its predictors

A total of 318 women developed ‘any SIL’ during their follow-up, leading to an incidence rate of 9.9 cases per 100 PY (95% confidence interval [IC], 8.8–11.0). Incidence was almost 2-fold higher among HRHPV-positive (14.8 per 100 PY, 95% IC 12.5–17.5) compared to HPV-negative women (7.9 per 100 PY, 95% IC 6.8–9.1).

Results from univariate and multivariate analysis for any SIL predictors are presented in Table 2. Women with a HRHPV positive status had 1.7-fold increased risk of presenting any abnormal cytology during the follow-up compared to women with no HRHPV at baseline in the adjusted model. Other predictors were: age (0.8, 95% CI 0.7–1) and age at first sexual intercourse (0.7, 95% CI 0.5–0.9). Incidence of any SIL decreased as current CD4+ count increased, mainly with counts from 0 to 600cells/μL (Fig. 1). This effect tends to stabilize for CD4+ counts above 600cells/μL (Fig. 1). LRHPV was considered as a confounder and remained in the final model. Additional analysis did not find interaction between HRHPV and both the linear term of CD4 and LRHPR.

Table 2.

Univariate and multivariate predictors of any SIL in a Brazilian HIV-infected women's cohort, 1996–2012.

Characteristics	Univariate		Multivariate
	RR (95% CI)	p-Value	RR (95% CI)	p-Value
HRHPV positive status	1.9 (1.5–2.4)	<0.001	1.7 (1.3–2.2)	<0.001
Age, years	0.8 (0.7–0.9)	0.002	0.8 (0.7–1)	0.01
Race/color
White	1
Non-white	0.9 (0.8–1.2)	0.61
Schooling, years
<9	1
9+	1.0 (0.8–1.2)	0.68
Positive LRHPV status	1.6 (1.2–2.2)	0.004	1.2 (0.9–1.7)	0.25
Age at first sex, years	0.5 (0.4–0.8)	<0.001	0.7 (0.5–0.9)	0.02
N. sexual partners in the last 6 months
0	1
1+	1.3 (1.0–1.7)	0.08
Current use of hormonal contraception
No	1
Yes	1.0 (0.7–1.5)	1.0
Smoking (ref=never)
Former	1.2 (0.9–1.6)
Current	0.9 (0.7–1.2)
Nadir CD4 T-cells count	1.0 (1.0–1.0)	0.66
Current CD4 T-cells count	Non-linear	<0.001	Non-linear	<0.001
Detectable HIV viral load in the last 12 months	0.8 (0.6–1.0)	0.03
cART use at baseline (ref=yes)	1.0 (0.8–1.3)	0.7

SIL, squamous intraepithelial lesion; HSIL, high grade squamous intraepithelial lesion; HRHPV, high risk HPV; LRHPV, low risk HPV; cART, combination antiretroviral therapy.

Fig. 1.

Relatives rates of any SIL (A) and HSIL+ (B) according to CD4+ cell-count in a Brazilian HIV-infected women's cohort, 1996–2012.

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Our results evidenced that HRHPV may be useful for screening cervical abnormalities among HIV-infected women. In our cohort, HIV-infected women presented low incidence rates of cytological abnormalities in a long-term follow-up. Incidences of any cytological and high grade abnormalities were significantly higher among those women with a positive HRHPV test. A single negative HRHPV test at baseline helped to identify women with a lower risk for developing any cytological and high grade abnormalities during a 12 and 36-months follow-up. To our knowledge, this is the first study to evaluate the use of HRHPV testing as a tool for cervical cancer screening in a clinical cohort of HIV-infected women in Latin America.

Our incidence rates of cytological abnormalities concord with previous studies. A systematic review of 15 studies among HIV-infected women identified any SIL and HSIL+ incidence rates ranging from 4.9 to 21.1 cases per 100 women-years and from 0.4 to 8.8 cases per 100 women-years, respectively.26 Pooled data showed higher rates of any SIL and HSIL+ among HIV-infected women when compared to their HIV-uninfected counterparts.26 However, even though the incidence of high-grade cervical lesions was higher in HIV-infected women, high-grade cervical lesions were uncommon, especially after regular screening initiation.10

Although some studies described higher false negative rates of cervical cytology among HIV-infected women when compared to HIV-uninfected counterparts,27,28 others, including more recent reports, have shown similar rates among HIV-infected and uninfected women.29–33 Regardless this controversy, cytology has been the method of choice for cervical cancer screening in all populations, including HIV-infected women.13 Recently, the Brazilian recommendations reaffirmed the role of cytology for cervical cancer screening among HIV-infected women.16 Nonetheless, there is a need to improve cervical cancer screening in Brazil toward a better coverage and earlier diagnosis. Clinical and economic studies have suggested to include HRHPV testing by Hybrid Capture as a complement in identifying high-risk cases for cervical cancer.18,34

Our results show that the NPV of a single HRHPV test was high for both the 12 and 36-months intervals, especially for HSIL+ (>99%). Indeed, we found that the most significant predictor of any SIL and HSIL+ abnormalities was the detection of a HRHPV at baseline. Women with a positive HRHPV test had, respectively, 2- and 5-fold increased risk of any SIL and HSIL+ during a 36-months interval. That is, a single negative HRHPV test helped to reassure 36 months of follow-up free of cytological abnormalities in HIV-infected women with a negative cytology. These findings corroborate results previously described in a HIV-infected cohort from a high-income setting. Keller et al. suggested that HIV-infected women with normal cytology and a negative HRHPV test have a risk of cervical abnormalities that is similar to that found in HIV-uninfected women through five years of follow-up.35 Similarly, Harris et al. found low any SIL incidence rates among women with normal cytology and negative HRHPV testing at baseline, which was similar for both HIV-uninfected and infected women with baseline CD4 cell counts higher than 500cells/μL.2 In contrast, authors found that HIV-infected women with normal cytology and a positive test for HPV 16 have a high risk of presenting with a high-grade lesion and recommended immediate referral for colposcopy.36

Our results also show that as current CD4+ count increases from 0 to 500cells/μL the risk of presenting any SIL and HSIL+ decreases. Higher rates of HPV infection were associated with lower current CD4+ count.7 A systematic review identified that most studies showed an association between lower CD4+ counts and increased incidence of cytological abnormality, although most estimates were not statistically significant.26 Massad et al. observed a progressive rise in cervical intraepithelial neoplasia outcomes as CD4+ counts fell, when adjusted for as a time-varying factor.10 Although careful cervical screening must be recommended for HIV-infected women, these authors consider that more aggressive intervention may be suggested in the context of severe immunosupression.10

Our study is not without limitations. Importantly, given that our main outcome is cytology-based, misclassification bias might have influenced our results. In a metanalysis, cervical cytology had lower sensitivity than other screening methods in primary cervical screening.37 Raposo et al. found similar results in HIV-infected women.38 However, as cytology-based cervical abnormalities continue to be the trigger for clinicians for further investigations, our results directly relate to clinical practice. Moreover, all cytology exams were performed in the same laboratory, so we do not expect misclassification biases differences within the HRHPV-positive and negative groups. Considering that multiple HPV infections are more common in HIV-infected women1,39 and that Hybrid Capture, the HPV testing used in our study, may present cross-reaction with HPV types other than the 13 targeted by the method,40,41 some samples may have been misclassified as HPV-positive, and incidence rates of cytological abnormalities could have been underestimated in the HPV-negative group. However, this cross-reactivity seems to have little significance on the overall clinical performance of the test.40 Although our cohort follows a standard interval schedule for clinic visits, screening intervals were not completely homogeneous. Nevertheless, the median time between visits was seven months (IQR 6–11) and likely did not influence results much given cervical abnormalities’ slow progression. Lastly, an unexpected result of our study was the protective association of a detectable viral load with incident SIL and HSIL, which may be due to our single-point assessment of HIV viral load in the last 12 months.

Even with the shift toward longer intervals for cervical cancer screening for uninfected women and the increasing body of data reinforcing the extension of screening intervals for HIV-infected women in care, especially for those with high CD4+ counts, most recommendations for HIV-infected women remain based on expert opinions and unchanged over the years worldwide. Other questions surrounding cervical screening in the HPV vaccination era, such as a change in the cytology performance, have also been raised.42 Since 2015, HPV vaccine is available at no cost for all HIV-infected women in Brazil. Thus, HRHPV testing may play a major role in our context. It is of major importance that cervical screening guidelines aggregate data regarding cervical screening among HIV-infected women in the post-HPV vaccine cART era, particularly in low and middle income settings.

The authors declare no conflicts of interest.