16. Screening in immune-deficient women

This section refers to women with acquired immune deficiency because of viral infection (e.g. human immunodeficiency virus (HIV)) or treatment with immunosuppressant drugs to prevent transplant rejection or to control an autoimmune disease (e.g. rheumatoid arthritis), as well as inherited primary immunodeficiency disorders (e.g. common variable immunodeficiency). Research on immune deficiency and cervical cancer has mostly focused on women with HIV and renal transplant recipients. 

Cervical prevalence of oncogenic human papillomavirus (HPV) in HIV-positive women without cytological abnormalities is higher than their counterparts from the general population.^[1][2] Shared behavioural risk factors for HIV and HPV potentially play some role in these observed differences. While HPV16 remains the most common type, in infected women with cytological abnormalities there appears to be a shift in the prevalence of HPV oncogenic types from HPV16 to other high risk types and a higher risk of multiple HPV infections with increasing severity of cervical disease; in a meta-analysis of 20 studies, HIV-positive women with a cytological prediction of high-grade squamous intraepithelial lesion (HSIL) were significantly more likely to have a positive oncogenic HPV (not 16/18) test result and to have multiple HPV infections, compared with HIV-negative women with HSIL.^[1] In renal transplant recipients, prevalence estimates of oncogenic HPV types vary, with some studies finding estimates similar to the general population^[3][4][5] and others reporting higher estimates.^[6] Shared behavioural risk factors for HIV and HPV potentially play some role in these observed differences.

HIV infection has been consistently associated with HPV infection and pre-cancerous cervical lesions,^[7][8][9] and a significantly higher rate of cervical cancer in women with HIV/acquired immune deficiency syndrome (AIDS) was reported in a meta-analysis of six population-based studies (incidence ratio: 5.8).^[10] High incidence rates of cervical cancer have been reported by some subsequent studies,^[11][12] although others have found incidence to be the same as in the general population.^[13] Antiretroviral therapy (ART) and highly active antiretroviral therapy (HAART) do not appear to have reduced cervical cancer incidence in women with HIV/AIDS^[14][15][16] and a systematic review by Cobucci (2015)^[17] found that the risk of invasive cervical cancer has increased since the introduction of HAART (RR=1.46, 95%CI: 1.09–1.94). In the past, ART/HAART was only prescribed to people with a low CD4 count, and this is likely to have influenced results of previous studies. Since 2015, however, HAART has been recommended for anyone living with HIV, irrespective of CD4 count. 

In solid organ transplant recipients, the majority of population-based studies have reported a higher incidence of cervical cancer than in their immunocompetent counterparts (standardised incidence ratios between 2–3).^[18][10][19] In contrast, a large US cohort study, using linked data from national and local registries, found the same incidence in transplant recipients as in the general population.^[20] There is also some evidence of a higher incidence of cervical intraepithelial neoplasia (CIN) in organ transplant recipients, although more research in this area is needed.^[21] 

Screening appears to play an important role in whether or not risk is increased compared to the general population, with studies in screened populations suggesting no difference in risk^[20][22][23] in contrast to other studies that have identified higher risks of cervical cancer.^[10] 

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The literature searches were performed to identify data for HIV-positive women and transplant recipients, because these groups were identified as being immune-deficient in the pre-renewal National Cervical Screening Program (NCSP) guidelines^[24] and are the predominant focus of research activities. 

Systematic review evidence

Two systematic reviews were performed to identify studies that evaluated the safety and effectiveness of screening HIV-positive women and organ transplant recipient women using a modified recommended screening strategy (starting at an age less than 25 years and/or screening at intervals less than 5 years and/or referring all women with a positive oncogenic HPV test result to colposcopy irrespective of reflex liquid based cytology (LBC) result), compared with the recommended screening strategy for the general population. The search strategies and inclusion and exclusion criteria used are described in detail in the Technical report.

No randomised or pseudo-randomised controlled trials were found that evaluated the safety and effectiveness of screening immune-deficient women using strategies other than those recommended for the general population, compared with screening strategies used for the general population. 

General literature review evidence

In the absence of any direct evidence from the systematic review, a general review of the literature was performed investigating cervical screening and the risk of progression among HIV-positive women and transplant recipients.

In the Women’s Interagency HIV Study, the risks of CIN2+ and CIN3+ were assessed among women with normal cervical cytology, according to HIV status and oncogenic HPV status at baseline. HPV status was ascertained from cervicovaginal lavage samples: ^[25][26] 

• In women in whom oncogenic HPV was not detected, the 5-year cumulative risk of CIN2+ and CIN3+ was the same, regardless of HIV status and CD4 count, and was less than 1% in both HIV-negative women and HIV-positive women, including in each CD4 count stratum (< 350, 350–500, and >500).^[26][25]
• In women with a positive oncogenic HPV test result, the 5-year cumulative risk for CIN2+ was 16% (95% CI:9–23%) in HIV-positive women versus 10% (95% CI:0–21%) in HIV-negative women.^[25]
• In multivariate analyses, there was no clear gradient in increasing risk for CIN2+ or CIN3+ with decreasing CD4 counts.^[25] 
• Among HIV-positive women who were positive for HPV16, the 5-year cumulative risks for CIN2+ and CIN3+ were 29% (95%CI:6-46) and 10% (95%CI:0-23) respectively.^[25][26]

Other studies have reported that clearance of oncogenic HPV types other than 16/18 appeared to differ in immune-deficient women, compared with other women, however clearance of HPV16 infections did not.^[27][28][29] In HIV-positive women, progression from low-grade cytological abnormalities to a higher-grade abnormality (either cytological or histological) appears to increase and regression to negative cytology appears to decrease with lower CD4 counts.^[30]

In regard to the performance of HPV testing (Hybrid Capture 2) for detecting high-grade CIN in women with HIV, sensitivity was reported to be somewhat greater in HIV-positive women (96.4% for CIN3; 99.2% for CIN2+) than in HIV-negative women (90.9% for CIN3; 85.5% for CIN2+), and the negative predictive value was high in both HIV-positive and HIV-negative women (99.8% and 99.5% respectively for less than CIN2). Specificity was lower in HIV-positive women. However, the positive predictive value of HPV testing in detecting CIN2 or CIN3 was equally as high in HIV-positive as in HIV-negative women.^[31] 

It has been hypothesised that the difference in incidence of cervical cancer in immune-deficient women observed between studies may be due to the extent to which the women included in the different studies have been screened.^[29][32] Low participation in cervical screening by HIV-positive women and transplant recipients has been reported in some studies.^[33][34][35] The influence of screening on risk is also indirectly supported by findings from studies reporting that risk in immune-deficient women is much more elevated for non-cervical HPV-related cancers (e.g. anal, vaginal, vulval, for which effective screening is not available) than for cervical cancer, even though the HPV attributable fraction for these cancers is lower than for cervical cancer.^[36][20] 

A review of international guidelines was also performed. The review focused on guidelines for HPV-based screening for immune-deficient women, as these guidelines are the most relevant for the renewed NCSP. Two recent guidelines now include recommendations for HPV-based screening, and both guidelines recommend a three-year interval for HIV-positive women: 

• The World Health Organization (WHO 2013) recommends that sexually active HIV-positive women should be screened as soon as the woman has tested HIV positive and those who are HPV-negative to be rescreened within 3 years.^[37] 
• Recent US guidelines recommend 3-yearly co-testing with HPV and cytology for HIV-positive women aged 30 years or older.^[38]

The evidence regarding screening and treatment to prevent cervical cancer in immune-deficient women is of lower quality than that in the general population, due to the absence of long-term randomised controlled trials comparing screening strategies in these women. Given that the evidence is unclear about the safety of lengthening the screening interval to 5 years for immune-deficient women, and that two international guidelines recommend a 3-year interval in the context of HPV testing in this population, it is considered safer to retain a 3-yearly interval in the renewed NCSP until further evidence about the negative predictive value of HPV testing in this population is better understood.

The US guidelines recommend 3-yearly co-testing^[38] but the review of the evidence carried out in Australia for the Medical Services Advisory Committee (MSAC) suggests that co-testing offers little additional benefit, compared with HPV testing alone. This is in line with other international recommendations and, therefore, co-testing is not recommended in this population or the wider program, as oncogenic HPV testing alone offers very similar benefits to co-testing.^[37] Therefore, the 3-year interval recommendation in this guideline is in accordance with WHO guidelines and supported by US guidelines for screening and treatment of precancerous lesions for cervical cancer prevention in HIV-positive women.

The following recommendations apply to the following groups:

• women with HIV
• solid organ transplant recipients.

These groups have been defined as sufficiently immune-deficient to warrant more frequent screening and a lower threshold for colposcopy referral than the general female population, based on current literature and pre-renewal NCSP guidelines.^[24] Note that this list is not exhaustive and does not include all patients with auto-immune conditions. 

Flowchart 16.1. Management of screen detected abnormalities in immune-deficient women

Screening interval recommendations

Management of abnormalities

Special recommendations

See also:

• Management of low-grade squamous abnormalities
• Management of high-grade squamous abnormalities
• Management of glandular abnormalities

There is evidence of an increased risk of CIN in immune-deficient women, but evidence is also suggestive that screening plays an important role in reducing or removing excess risk of cervical cancer. The current recommendations will ensure the prompt treatment of any precancerous lesions before progression to cervical cancer. Diagnostic assessments and potential treatment required in these women, currently under increased surveillance for their underlying disease, may cause additional anxiety and distress. 

However, it is generally considered that the benefits outweigh the harms for immune-deficient women. 

See the Chapter 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed National Cervical Screening Program (NCSP).

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Clinical practice

Recommendations regarding the management of immune-deficient women are consistent with present clinical practice.

Resourcing

No additional costs are anticipated.

Barriers to implementation

Some immune-deficient women may choose not to attend for cervical screening as frequently as recommended. Less frequent screening has been reported in both women with HIV and organ transplant recipients.^[33][34][35] 

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There is some evidence to support increased progression of cervical abnormalities in HIV-positive women compared with HIV-negative women.^[30] Although HAART has been in use for two decades, there is only limited evidence of an increased likelihood of lesion regression and a higher clearance rate of oncogenic HPV positive SIL in adherent users.^[30][39][40] Overall, there is insufficient direct evidence to support a change from the screening recommendations in pre-renewal NCSP guidelines,^[24] which recommended colposcopy referral for any screen-detected abnormality. 

When CIN is diagnosed in HIV-positive women, excisional therapy is recommended. However, failure rates are high, necessitating frequent post-treatment surveillance. Massad et al^[41] reported that most lesions detected after therapy in HIV-positive women were low grade which may be indicative of new HPV infections that are less likely to progress. 

The burden of HPV-related cancers can be expected to increase in HIV-positive women given successful prolongation of life with ART and potentially longer duration of HPV persistence.^[38] 

Unresolved issues

There is insufficient evidence available to determine the optimal cervical screening strategy in immune-deficient women. Current recommendations reflect a cautious approach until further data become available. The effect of ART on progression of cervical disease is still unclear. 

These guidelines have not investigated the need for special consideration in other groups of women who may be immune deficient either due to a disease, immunosuppressive drugs or both. This group is heterogeneous due to by varying degrees of disease severity, duration, types and length of treatments.

Future research priorities

Long-term randomised controlled trials, comparing screening strategies in immune-deficient women, are needed to inform future guidelines. It is anticipated that the renewed NCSP and the National Cancer Screening Register will facilitate the collection of data on immune-deficient women to support future recommendations. Modelled analysis may help in determining whether routine 5-yearly screening could be suitable for this group of women.

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