Oncogenic HPV types not 16/18

Women who have a positive oncogenic human papillomavirus (HPV) test result for which HPV types other than 16 and/or 18 are detected (‘HPV not 16/18’), should be managed according to the recommendations in this section. 

Women who have a positive oncogenic HPV test result indicating the presence of both HPV type 16 and/or 18 and other oncogenic HPV types (not 16 /18), for example, a woman whose test indicates the presence of types 16 and/or 18 and 31, or 18 and 33), should be managed as for HPV types 16/18 (see Oncogenic HPV types 16/18). 

Some HPV test platforms may provide additional channels with information on some of the other oncogenic HPV types (e.g. Type 31, 33 and/or 45). For the purposes of these guidelines, these HPV types should be considered as ‘oncogenic HPV (not 16/18)’ and women with these types should be managed accordingly. 

These guidelines incorporate recommended HPV, cytology and histopathology terminology (see 3. Terminology).

2016 analysis

MSAC recommended liquid-based cytology (LBC) triage for women with a positive oncogenic HPV (not 16/18),[1] but made no recommendations for subsequent management on the basis of triage LBC. 

For some groups of women, it may be safe to delay colposcopy and monitor risk with follow-up surveillance, as distinct from women with a positive oncogenic HPV (16/18) test result, for whom MSAC recommended immediate colposcopy (see Oncogenic HPV types 16/18).

HPV infections typically clear rapidly. Overall, an estimated 67% of infections resolve by 12 months, although the rate of resolution probably varies between age groups and by HPV type. After viral clearance (i.e. oncogenic HPV is no longer detected), women are at very low risk of significant cervical disease for the next 5 years. Therefore, if women with a positive oncogenic HPV (not 16/18) test result are not referred to colposcopy immediately, 12 months is an appropriate follow-up interval for retesting and allows for viral clearance to occur in a proportion of women. 

The modelled MSAC evaluation of partial genotyping strategies made the following assumptions:

• Women with pHSIL or a higher-grade lesion on LBC are referred for immediate colposcopy, irrespective of HPV type. This assumption is standard-of-care because these women are already known to be at risk of a high-grade lesion. Within the prerenewal National Cervical Screening Program (NCSP), women with pHSIL are referred to immediate colposcopy.
• Women with a positive oncogenic HPV (not 16/18) test result who have negative LBC undergo follow-up surveillance at 12 months rather than immediate colposcopy.

The MSAC evaluation also modelled alternative management options for women with a LBC prediction of possible low-grade intraepithelial lesion (pLSIL) or low-grade intraepithelial lesion (LSIL) and a positive oncogenic HPV (not 16/18) test result. These women are at intermediate risk of significant cervical abnormality (see Section 3. Terminology). MSAC did not make recommendations for the follow-up of this group of women.[1] Therefore, further systematic reviews and modelling analyses were undertaken to inform recommendations for this group. The updated modelled analysis considers the management pathways for colposcopy referral, colposcopic management, and post-treatment test-of-cure as specified in these guidelines, some of which differ from the assumptions made in the MSAC modelling. Therefore, the final modelled analysis considers the impact of changing recommendations for this group on outcomes and costs (see Section 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed NCSP and Modelling reports.)

2020 analysis

In April 2020, the NCSP reviewed program data relating to biopsy outcomes in women referred to colposcopy following persistent detection of oncogenic HPV (not 16/18) at their 12-month follow-up HPV test, where LBC was either negative, pLSIL or LSIL.[2] 

As a result, an update was made to the management of HPV (not 16/18) – such that if HPV (not 16/18) continues to be detected at 12 months and reflex LBC does not predict a possible highgrade squamous intraepithelial lesion (pHSIL), high-grade squamous intraepithelial lesion (HSIL), cancer or a glandular abnormality, women can safely be retested in a further 12 months before being referred to colposcopy if HPV detection persists at that time.

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Initial evidence review

Systematic reviews and modelling studies were initially undertaken to assess the comparative safety and effectiveness of different strategies based on LBC triage in women with a positive oncogenic HPV (not 16/18) test result. 

In the initial evaluation, for women with a positive oncogenic HPV (not 16/18) test result and LBC prediction of pLSIL/LSIL, we compared the following strategies:

• immediate colposcopy
• 12-month follow-up and referral to colposcopy if follow-up HPV testing is positive (regardless of HPV type) at 12 months.

In the initial evaluation, for women with a positive oncogenic HPV (not 16/18) test result who do not undergo immediate colposcopy, we compared the following strategies:

• repeated HPV testing at 12 and 24 months before returning to 5-yearly screening if negative at both follow-up tests
• repeated HPV testing at 12 months only, before returning to 5-yearly screening if negative at 12 months.

Evidence update (non-systematic review)

In a subsequent (April 2020) evaluation of emergent National Cancer Screening Register (NCSR) data from the renewed NCSP, we considered the following modification in management for women with a positive oncogenic HPV (not 16/18) test result who do not undergo immediate colposcopy, and who have a follow-up HPV testing at 12 months where the follow-up HPV test is positive for oncogenic HPV (not 16/18):[2]

• Where reflex LBC at 12 months predicts pHSIL, HSIL, cancer or a glandular abnormality – colposcopy referral is recommended (no change in management)
• Where reflex LBC at 12 months does not predict pHSIL, HSIL, cancer or a glandular abnormality – a second follow-up HPV test in a further 12 months is recommended (i.e. 24 months after the initial screen). If HPV detection persists at the second follow-up test, it is recommended that women are referred for colposcopy, regardless of the result of reflex LBC.

Women who may be at higher risk of harbouring a high-grade abnormality should be referred to colposcopy if HPV is detected at 12 months, regardless of the result of reflex cytology. This includes the following groups:

• Women two or more years overdue for screening at the time of the initial screen
• Women who identify as being of Aboriginal or Torres Strait Islander descent
• Women age 50 years or older

There are other groups of women who fall outside these recommendations with separate guidance, including:

• Immune deficient women
• Women exposed to diethylstilboestrol (DES) in utero
• Women currently undergoing Test of Cure following treatment of histological HSIL
• Women aged 70-74 (attending for an exit test)
• Women aged 75+

Evidence findings

Systematic review

The systematic literature search identified no randomised or pseudo-randomised controlled trials directly addressing either of the following:

• the safety and effectiveness of immediate colposcopy for women with a positive oncogenic HPV (not 16/18) test result and a reflex LBC prediction of pLSIL/LSIL, compared with 12 months’ delay.
• the safety and effectiveness of repeating HPV testing after 12 and 24 months for women with a positive oncogenic HPV (not 16/18) test result and LBC reported negative or with a prediction of pLSIL/LSIL, compared with repeating HPV testing at 12 months only, before returning to 5-yearly screening.

The search strategies and inclusion and exclusion criteria are described in detail in the Technical report.

In the absence of studies directly addressing these issues, an indirect approach to the literature review was planned which focussed on benchmarking (i.e. assessing the underlying risk threshold for abnormalities that may develop into cervical intraepithelial neoplasia grade 3 (CIN3) or invasive cancer, which was accepted in the pre-renewal NCSP as requiring colposcopy referral). Similarly, we sought evidence on the benchmark (lower) risk level for which, in the pre-renewal NCSP, it was accepted that 12-month follow-up was appropriate. These ‘benchmark’ risks were compared with the risks in women in the renewed NCSP with LBC reported negative or with a prediction of pLSIL/LSIL and a positive oncogenic HPV (not 16/18) test result.

Risk benchmarks were considered for women with a positive oncogenic HPV (not 16/18) test result and a reflex LBC prediction of pLSIL/LSIL:

• 12-month follow-up benchmark: as recommended for women with LSIL cytology in the pre-renewal NCSP.[3]
• Colposcopy referral benchmark 1 (cytology prediction of pHSIL/HSIL): as recommended (and considered standard-of-care) in the pre-renewal NCSP[3]
• Colposcopy referral benchmark 2 (positive oncogenic HPV (16/18) test result): as recommended by MSAC in the renewed NCSP.

Systematic reviews were performed to identify studies examining the risk for the development of CIN3+ (CIN 3 or invasive cervical cancer) among women with a positive oncogenic HPV (not 16/18) test result and pLSIL/LSIL cytology, compared with each of the following groups:

• women with cytological prediction of pLSIL/LSIL, regardless of HPV status
• women with cytological prediction of pHSIL/HSIL, regardless of HPV status
• women with a positive oncogenic HPV (16/18) test result, regardless of cytology status.

The search strategies and findings are described in detail in the Technical report.

Searches identified six relevant prospective cohort studies (level II evidence): two longitudinal studies[4][5] and four studies that reported results for outcomes on immediate colposcopy.[6][7][8][9][10][11][12][13][14] None of these studies were specifically designed to compare the risks associated with specific oncogenic HPV genotypes and specific cytology findings. As a result, it was not possible to determine whether subgroups with oncogenic HPV types (not 16/18), pLSIL or LSIL were similar to benchmark groups or to control for confounding factors such as smoking. Therefore, all six studies were assessed to have a high risk of bias.

Both longitudinal studies reported CIN3+ risks associated with oncogenic HPV (not 16/18), LSIL cytology and, for the benchmark for 12-month follow-up, all LSIL cytology, regardless of HPV status. In one study women were actively followed up for 2 years and underwent an exit colposcopy,[4] and in the other women were passively followed-up for a maximum of 18 years.[5] 

Two studies[6][7][8][9][10][14] reported CIN3+ risks on immediate colposcopy for women with a positive oncogenic HPV (not 16/18) test result, pLSIL (ASC-US, Bethesda 2001) or LSIL cytology and the benchmarks for immediate colposcopy (pHSIL/HSIL cytology or positive HPV (16/18) test result), as well as the benchmark for 12-month follow-up (all LSIL). 

The findings of these studies showed the following:

• For women with a positive oncogenic HPV (not 16/18) test result and a cytological prediction of LSIL, the risk of CIN3+ was lower than that for the 12-month follow-up benchmark (LSIL cytology, regardless of HPV status):
  • over 2 years in cohorts age >18 years or >30 years at baseline
  • after 18 years in a cohort age >16 years at baseline.
• For women with a positive oncogenic HPV (not 16/18) test result and a cytological prediction of pLSIL/LSIL, the risk of CIN3+ diagnosed on immediate colposcopy was consistently less than half the risk for the immediate colposcopy benchmarks (cytological prediction of pHSIL/HSIL or positive oncogenic HPV (16/18) test result) and similar to (if not less than) the 12-month follow-up benchmark (cytological prediction of LSIL, regardless of HPV status) in cohorts age >25 years, >21 years or >18 years at baseline.

A second systematic review was performed to identify studies examining the risk of CIN3 or higher-grade lesion among women undergoing routine cervical screening with a positive oncogenic HPV (not 16/18) test result and negative cytology, compared with the following groups:

• 12-month follow-up benchmark (women with a cytological prediction of pLSIL/LSIL, regardless of HPV status)
• women with a cytological prediction of pLSIL/LSIL and a positive oncogenic HPV (not 16/18) test result.

No studies that met inclusion criteria were identified. The search strategy and findings are described in detail in the Technical report.

Modelling

The findings of the systematic review confirmed that a modelled analysis was required to assess the safety and effectiveness of immediate colposcopy, compared with returning in 12 months for a repeat HPV test, for women with a positive oncogenic HPV (not 16/18) test result and reflex LBC prediction of pLSIL/LSIL at triage. The modelling study assessed the population level effects of alternative strategies, within a national program of primary HPV screening with partial genotyping, for women with a positive oncogenic HPV (not 16/18) test result and reflex LBC prediction of pLSIL/LSIL. Modelling was performed for HPV-unvaccinated women and for cohorts offered vaccination.

Options compared in women with a positive oncogenic HPV (not 16/18) test result and reflex LBC prediction of pLSIL/LSIL

Comparison 1:

• (Option A) follow-up with HPV testing in 12 months, followed by colposcopy for those with a positive oncogenic HPV (any type) test result at 12 months, or return to routine 5-yearly screening if oncogenic HPV not detected at 12 months
• (Option B) referral to colposcopy.

Comparison 2:

• (Option A) as above
• (Option C) referral to follow-up with HPV testing in 12 months and 24 months, with immediate colposcopy for those with a positive oncogenic HPV (any type) test result at either follow-up test, or return to routine 5-yearly screening if oncogenic HPV not detected at both follow-up tests.

Summary of findings

The findings are described in detail in the Modelling reports.

Comparison 1: 12-month follow-up versus immediate colposcopy 

Modelling comparing 12-month follow-up with immediate referral to colposcopy in women with a positive oncogenic HPV (not 16/18) test result and reflex LBC prediction of pLSIL/LSIL predicted the following:

• For women in this group undergoing 12-month follow-up (Option A), the 20-year risk of developing invasive cervical cancer (Figure 6.1) is lower than the risk for women with a screening cytology prediction of LSIL in the pre-renewal NCSP (i.e. lower than the accepted benchmark risk for 12-month follow-up in Australia).
• The renewed NCSP, incorporating 12-month follow-up for women in this group (and incorporating other recommendations in these guidelines), is predicted to reduce cervical cancer incidence and mortality by 31–36% in unvaccinated cohorts and 24–29% in cohorts offered vaccination, compared with the pre-renewal NCSP.
• The renewed NCSP, incorporating immediate colposcopy for women in this group (and incorporating other recommendations in these guidelines), is predicted to reduce cervical cancer incidence and mortality by 32–37% in unvaccinated cohorts and 27–32% in cohorts offered vaccination, compared with the pre-renewal NCSP.
• For women in this group, immediate referral to colposcopy provides an incremental 1–3% reduction in cervical cancer incidence and mortality, compared with 12-month follow-up. However, colposcopy referral for this group substantially increases the number of colposcopies in the renewed NCSP, with more than 650 colposcopies required to avert an additional case of cervical cancer, compared with 12-month follow-up.
• Colposcopy referral for this group would be very cost-ineffective, with an incremental cost-effectiveness ratio of >$100,000 per life-year saved (LYS), compared with 12-month follow-up.
• Colposcopy referral of only women age >45 years in this group, however, is more cost-effective, with an incremental cost-effectiveness ratio of $40,000/LYS (95% credible interval (CrI): $37,000–42,000/LYS) in unvaccinated cohorts, and $41,000/LYS (95% CrI: $38,000–44,000/LYS) in cohorts offered vaccination.

Figure 6.1. Predicted 20-year risk of cervical cancer in women with a positive oncogenic HPV (not 16/18) test result and a reflex LBC prediction of pLSIL/LSIL

Note: The black horizontal line in each figure indicates the risk under the pre-renewal NCSP for women with a cytological prediction of LSIL at a routine screening visit and a negative cytology test in the previous 2 years.

Comparison 2: follow-up options (12 and 24 months versus 12 months only)

Comparison 2: follow-up options (12 and 24 months versus 12 months only) Modelling comparing follow-up at both 12 months and 24 months, with 12-month follow-up only, in women with a positive oncogenic HPV (not 16/18) test result and reflex LBC prediction of pLSIL/LSIL at index screening visit predicted the following:

• Performing both 12-month and 24-month follow-up results in <1% difference in cervical cancer incidence and mortality and <1% difference in colposcopies, compared with 12-month follow-up only.
• Performing both 12-month and 24-month follow-up for this group would be very cost-ineffective, with an incremental cost-effectiveness ratio of >$300,000/LYS, compared with 12-month follow-up only.
• Limiting both 12-month and 24-month follow-up to women over 55 in this group remains cost-ineffective compared with 12-month follow-up only. The incremental cost-effectiveness ratio is >$65,000/LYS if 12-month and 24-month follow-up is used in women age over 55 years, compared with performing 12-month follow-up only for women of all ages.

The detailed description of the model assumptions, calibration and findings are provided in the Modelling reports.

Although the update to these Guidelines in 2020 for the management of intermediate risk women who remain HPV positive at 12/24 months was not explicitly modelled, based on the 2020 NCSR data analysis (see below), the overall population-level benefits modelled for the renewed NCSP compared with the pre-renewed NCSP, are likely to be similar to those originally modelled.

Review of NCSP data

In 2020, a review of the first 2 years of the renewed NCSP was conducted on data for women classified as having higher or intermediate risk of cervical cancer on their baseline Cervical Screening Test with subsequent colposcopy and/or histology recorded on the NCSR. The following data were included:

• all results for women at higher risk and intermediate risk from 1 December 2017 to 31 December 2019 (data extracted 14 January 2020)
• all colposcopy assessment and MBS forms coded and completed by the NCSR relating to visits up to 16 April 2020 (data extracted 22 September 2020)
• and all histology assessment and MBS forms coded and completed by the NCSR relating to samples collected up to 16 April 2020 (data extracted 22 September 2020).

For benchmarking, the outcomes for intermediate risk women whose follow-up test result is HPV (not 16/18) were compared with outcomes in those women at higher risk at baseline (Tables 6.1, 6.2).[2]

Table 6.1. Outcomes for higher-risk group according to baseline test (based on April 2020 NCSR data)

Table 6.2. Outcomes for women initially at intermediate risk, whose follow-up test result is HPV (not 16/18), according to LBC prediction at follow-up test (based on April 2020 NCSR data)

The analysis shows that, compared with other groups who are referred for colposcopy, the risk of CIN2+, CIN3+ and cervical cancer are much lower for women at intermediate risk whose follow-up test is HPV (not 16/18) and who have an LBC prediction of negative, pLSIL or LSIL. Within this group of women, we compared risks for women age <50 years with those for women age 50 years or older (Table 6.3).[2]

Table 6.3. Outcomes for women initially at intermediate risk, whose follow-up test result is (HPV (not 16/18), and LBC prediction is negative, pLSIL or LSIL, according to age (based on April 2020 NCSR data)

It should be noted that women 50 years or older who are HPV positive without a visible lesion at colposcopy, are at higher risk of harbouring a covert abnormality in the canal (compared to younger women who are HPV positive). Considering this issue, and applying the precautionary principle, among women at intermediate risk whose follow-up test is HPV (non 16/18), LBC prediction negative, pLSIL or LSIL, direct referral to coloscopy should still be recommended for women 50 years of age or over. It is important to note that older women referred to colposcopy on this basis, who are likely to have a type 3 TZ, not undergo diagnostic excision of the TZ without histological or cytological evidence of a high-grade lesion (see Recommendation 8.12).

Additionally, other groups of women may be at higher risk of harbouring a high-grade abnormality, and again applying the precautionary principle, among women at intermediate risk whose follow-up test is HPV (non 16/18), LBC prediction negative, pLSIL or LSIL, direct referral to coloscopy should still be recommended for:

• Women two or more years overdue for screening at the time of the initial Cervical Screening Test
• Women who identify as being of Aboriginal or Torres Strait Islander descent

Women who identify as Aboriginal or Torres Strait Islander are known to have higher rates of cervical cancer incidence and mortality. There is a paucity of program-wide data on risk of high-grade abnormalities in Aboriginal or Torres Strait Islander women, due to a historical lack of data on Indigenous status in screening registers and continuing low levels of completeness of this information on the National Cancer Screening Register. Data from population-based linked health records in Queensland, however, document a higher risk of high-grade histological abnormalities among Aboriginal or Torres Strait Islander women (OR 2.0, 95% CI 1.9–2.1).[15] 

Note that there are other groups of women who fall outside these recommendations as there are separate guidelines specifically for them, including:

• Immune deficient women
• Women exposed to diethylstilboestrol (DES) in utero
• Women currently undergoing Test of Cure following treatment of histological HSIL
• Women aged 70+ (attending for an exit test)

*Note that grading of the evidence was performed according the NHMRC guidelines in place at the time of the original development of these guidelines (for consistency).
**2020 review of NCSP data.

Recommendations

Flowchart 6.4 Cervical screening pathway for primary oncogenic HPV screening (HPV tests on clinician-collected or self-collected samples): HPV (not 16/18) detected 

While all screening programs will fail to detect some cases, implementation of these recommendations does not present any significant concern about the potential for missed cancers. Rates of cervical cancer are low in Australia, compared with international rates.[16] Modelling, taking into account post-colposcopy management as recommended in these guidelines, has predicted that a 31–36% reduction in incidence and mortality may be achievable in unvaccinated cohorts and a 24–29% reduction may be achievable in cohorts offered vaccination (Section 2. The rationale for primary HPV screening and Section 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed NCSP).[17]

In 2005, the NCSP adopted a policy of 12-month follow-up for women with a cytological prediction of pLSIL/LSIL, replacing the previous policy of immediate referral to colposcopy. A recent evaluation by the NCSP Quality and Safety Monitoring Committee found that this policy was not associated with an increase in the incidence of cervical cancer in women age 20–69 years.[18] 

Within the renewed NCSP, the policy of 12-month follow-up for women with a LBC prediction of pLSIL/LSIL would apply only to the subgroup of women at intermediate risk of significant cervical abnormality based on HPV testing with partial genotyping, in contrast to the pre-renewal program in which the policy applies to an undifferentiated group of women with either high or intermediate risk. Accordingly, modelled results suggest that the risk for women with a positive oncogenic HPV (not 16/18) test result and a reflex LBC prediction of pLSIL/LSIL who have 12-month follow-up surveillance, is lower than the risk in women with a screening cytological prediction of LSIL in the pre-Renewal NCSP (i.e. the risk in this group is lower than the accepted benchmark risk for 12-month follow-up in Australia). 

More than half of women with an oncogenic HPV infection are expected to clear the infection within 12 months.[19] Those with persistent infection (or with an HPV infection detected on repeat testing) would be identified at the 12-month HPV repeat test.

The original prediction of low risk among women with oncogenic HPV (not 16/18) and a reflex LBC prediction of pLSIL/LSIL has been borne out by a 2020 review of NCSP data from the first 2 years of the renewed program. In fact, the risk of CIN2+ among women presenting for colposcopy following persistent detection of HPV (not 16/18), in the absence of pHSIL, HSIL, cancer of glandular abnormality on cytology, is low enough to justify a further 12 months of surveillance prior to referral to colposcopy. This change results in a better balance of benefits and potential harms by allowing women at very low risk of CIN2+ (and based on current data, very low risk of cancer) a further 12 months, by which time many women will have cleared the HPV infection and will then not require colposcopy at all. 

Implementation of these recommendations will avoid many unnecessary colposcopies and associated harms (including biopsy, overtreatment, anxiety and financial costs) for women with HPV-related cervical abnormalities that would resolve spontaneously without medical intervention.

Clinical practice

Colposcopic assessment and management will be more challenging in the renewed NCSP because there will be a higher proportion of women with a positive oncogenic HPV test result who have minimal or no cytological changes. Originally, all women with persistent infections with oncogenic HPV (not 16/18) were referred to colposcopy after 12 months and a very large proportion of these will represent HPV infection without neoplastic potential. This has been borne out in practice in the first 2 years of the renewed NCSP, placing considerable pressure on colposcopy services, with some women in this category therefore facing considerable delay in accessing colposcopy. The change, implemented in 2020, to allow a further 12 months of surveillance prior to referral to colposcopy is designed to safely relieve these pressures.

Resourcing

Updated modelling, taking into account these detailed guideline recommendations, and taking into account the reduction in HPV 16/18 infections due to vaccination in the population, has informed an assessment of the resourcing associated with partial genotyping strategies (see Section 5. Benefits, harms and cost-effectiveness of cervical screening in the renewed NCSP).

Barriers to implementation

Healthcare professionals may be reluctant to delay colposcopy in women who have a positive oncogenic HPV (not 16/18) test result, despite this being their current practice with low-grade cytology. Education of GPs and other healthcare professionals who provide cervical screening services, emphasising the safety of this approach, will be essential to the implementation of this recommendation. 

Some women may be reluctant to accept a 12-month delay in referral for colposcopy, especially if they are aware of their HPV test result. Education of women and careful explanation by their healthcare provider will be of paramount importance. 

GPs, other healthcare professionals and women participating in screening should understand that the recommendation to defer colposcopy (if needed at all) for 12 months is unchanged from accepted practice for women with an abnormal Pap test result predicting pLSIL/LSIL. 

Conversely, GPs may not refer women with a persistent positive oncogenic HPV (not 16/18) test result to colposcopy, but this risk will be mitigated by the laboratory report to the GP clearly recommending referral, and by existing registry follow-up with reminder letters as needed. 

Similarly, the women in this situation may not fully understand the need for colposcopy, especially if the reflex LBC result is negative, and may fail to attend. Patient education and registry reminder letters will play an important role in this situation. Effective communication with health professionals, and with affected women, will be necessary to implement the change in the pathway for women with HPV (not 16/18) detected and negative, pLSIL or LSIL cytology (Flowchart 6.1).

Colposcopy waiting lists will need to be re-prioritised and primary health providers may find that women previously referred to colposcopy are returned to primary care for a further follow-up HPV test. This will require careful communication. Laboratories will need to rework their procedures for reporting recommended management in these cases and for many laboratories a software adjustment will be needed, where decision support software is in place. The NCSR will also need to adjust its follow-up communications accordingly.