Management After HPV-Positive with Negative Pap Smear
For an average-risk woman aged 25-65 with a positive high-risk HPV test and negative Pap smear, two consecutive negative tests (either two negative HPV tests or two negative co-tests) are required before returning to routine screening intervals.
Initial Follow-Up Strategy
When a woman presents with HPV-positive but cytology-negative results, the recommended approach is:
- Repeat HPV testing with or without concurrent Pap testing in 1 year 1
- HPV testing or co-testing is preferred over cytology alone for follow-up after an abnormal result, as negative HPV testing is less likely to miss disease than normal cytology testing alone 1
Return to Routine Screening Criteria
For Women Aged 30-65 Years
The evidence consistently supports requiring two consecutive negative results before returning to routine screening:
- After 2 negative cytology results or a negative HPV test, return to annual screening initially 1
- For women managed with active surveillance who achieve regression, two consecutive high-risk HPV negative tests 12 months apart are required to discharge a woman back to a 3-year recall 1
- If high-risk HPV testing is negative at 3 years after discharge, the woman can return to routine recall which could include extended 5-yearly screening intervals 1
Specific Testing Intervals
- Cytology testing is recommended annually when HPV testing or co-testing is recommended at 3-year intervals 1
- Cytology testing is recommended at 6-month intervals when HPV testing or co-testing is recommended annually 1
Important Clinical Considerations
Risk Stratification by HPV Type
The management differs based on HPV genotype:
- HPV 16 is the highest-risk type: colposcopy is recommended in all cases, even if cytology is normal 1
- HPV 18 has relatively high association with cancer: colposcopy is recommended in all cases, even if cytology is normal, with endocervical sampling acceptable at time of colposcopy due to adenocarcinoma risk 1
- Other high-risk HPV types with normal cytology: return in 1 year is recommended in most cases 1
Long-Term Surveillance
A critical caveat often overlooked:
- After treatment for high-grade precancer, surveillance should continue for at least 25 years, regardless of negative test results 1
- Women with a history of high-grade lesions (CIN 2 or CIN 3) may warrant colposcopy even with negative screening results 1
Common Pitfalls to Avoid
Premature Return to Extended Intervals
- Do not return to 3-year or 5-year screening intervals after only one negative test 1
- The requirement for two consecutive negative tests is based on the understanding that approximately 60% of women who are high-risk HPV-positive will become HPV-negative during follow-up, but persistent infection carries higher risk 1
Misinterpreting Negative HPV with Abnormal History
- Colposcopy is still warranted if negative HPV test or co-test results occurred in the context of surveillance for a previous abnormal result, even if performed within the last 5 years 1
- Previous negative screening tests do not modify recommendations; colposcopy is always recommended for two consecutive HPV-positive tests 1
Inadequate Follow-Up Compliance
- Real-world data shows that only 47% of women with negative co-tests receive appropriate follow-up, and 30.8% of women with HPV 16/18 positive results receive no follow-up within 18 months 2
- Robust recall systems are essential to ensure women return for the required second negative test before extending screening intervals 2
Algorithm Summary
- Initial result: HPV-positive, cytology-negative (excluding HPV 16/18)
- First follow-up: Repeat HPV test ± Pap at 12 months 1
- If first follow-up negative: Repeat testing at 12 months (second negative test required) 1
- After two consecutive negative tests: Return to 3-year screening intervals 1
- If negative at 3 years: May extend to 5-year intervals until usual exit screening round 1
If HPV remains positive or cytology becomes abnormal at any point, proceed to colposcopy 1.