Primary HPV Testing Without Pap Smear: Evidence‑Based Recommendations

Preferred Screening Strategy

The American Cancer Society (2020) recommends primary HPV testing every 5 years as the preferred cervical‑cancer screening method for average‑risk women aged 25–65, without concurrent cytology. 1
The same guideline states that cotesting (HPV + Pap) every 5 years or cytology alone every 3 years are acceptable only where FDA‑approved primary HPV testing is unavailable, and these alternatives should be phased out as primary HPV testing becomes universally accessible. 1

After successive negative primary HPV tests, the 5‑year risk of CIN 3+ declines markedly: ≈0.073 % after the first negative, ≈0.042 % after two negatives, and ≈0.027 % after three negatives. [2][3]
An HPV‑negative result provides protection comparable to a negative cotest, regardless of the accompanying cytology result. 4

For women with HPV‑negative ASC‑US, the American Cancer Society (2019) advises repeat screening in 3 years, not the standard 5‑year interval used for a negative primary HPV test. 5
The risk profile of HPV‑negative ASC‑US is similar to that of a negative cytology alone and does not meet the low‑risk threshold of a negative cotest; therefore it is insufficient for exiting screening at age 65. [6][7]

Adding cytology to a negative primary HPV test offers only minimal incremental benefit and is not required in primary HPV screening protocols. 8
The American Cancer Society (2020) explicitly supports HPV testing as a stand‑alone test without concomitant cytology. 1

When cytology alone is used, screening should not be performed more frequently than every 3 years. [9][5]

Women with a prior history of CIN 2+ should continue surveillance for at least 20 years beyond the initial diagnosis. [9][5]
Immunocompromised individuals (e.g., HIV‑positive, organ‑transplant recipients, chronic corticosteroid users) require tailored screening strategies and cannot follow the average‑risk primary‑HPV‑only algorithm. [9][5]
Women with a history of cervical cancer or in‑utero DES exposure are excluded from the average‑risk primary‑HPV‑only recommendations. [9][5]

Women aged 30-65 years with negative HPV and negative Pap should undergo repeat cotesting in 5 years, as recommended by the guideline society, representing the preferred screening strategy for women in this age group with completely negative results 10
The American College of Obstetricians and Gynecologists recommends cotesting every 5 years as the preferred screening strategy, with an alternative acceptable approach being cytology alone every 3 years 10
The Centers for Disease Control and Prevention recommends that women with negative HPV and negative Pap test results should be retested in 5 years, as this represents the consensus guideline recommendation 11

To discontinue screening at age 65, patients must have either 3 consecutive negative cytology tests OR 2 consecutive negative cotests within the past 10 years, with the most recent test performed within the past 5 years, as recommended by the guideline society 10
Patients must have no history of high-grade squamous intraepithelial lesions (HSIL), adenocarcinoma in situ, or cancer to discontinue screening at age 65, according to the guideline society 10

The American Cancer Society recommends not confusing negative cotest results with HPV-negative/ASC-US results, which require a 3-year follow-up interval rather than 5 years, to avoid misinterpretation of test results 12, 13, 14
The guideline society recommends not extending the interval beyond 5 years for routine screening, even though the risk remains very low, as this represents the consensus guideline recommendation 10
The Centers for Disease Control and Prevention recommends not using cytology alone for follow-up when cotesting is available, as HPV testing or cotesting provides superior reassurance compared to cytology alone 11

After treatment for high-grade precancer, the guideline society recommends initial testing at 6, 18, and 30 months, followed by long-term surveillance at 3-year intervals for at least 25 years, as this provides adequate monitoring for potential recurrence 11
The extended surveillance continues even beyond age 65 years if the 25-year period has not been completed, as recommended by the guideline society, to ensure long-term follow-up 11

Co‑testing with cytology + high‑risk HPV every 5 years is the preferred approach, providing the longest safe interval between screens. 15, 16, 17, 18
Adding HPV testing to cytology increases detection of prevalent high‑grade lesions (CIN 3+) while reducing detection in subsequent rounds, thereby lowering the post‑negative‑screen risk. 17, 19

Cytology alone every 3 years remains acceptable but is not preferred because it requires more frequent testing and offers less reassurance than co‑testing. 15, 17, 19

Cytology alone every 3 years is recommended; HPV testing (alone or in combination) should not be used in this age group. 16, 18

Screening may be stopped at age 65 only if all of the following are met:
Once screening is discontinued after age 65, it should not be resumed for any reason, including a new sexual partner. 16, 18

Women with a history of CIN 2 or higher must continue routine screening for at least 20 years after the initial diagnosis, even if this extends beyond age 65. 16, 18

The interval for routine co‑testing must not exceed 5 years; evidence does not support longer intervals. 15, 17, 19
Cytology alone should not be performed more frequently than every 3 years; annual or biennial screening markedly increases colposcopy referrals without a meaningful reduction in cancer mortality (predicted lifetime cancer death: 0.03 / 1000 for annual vs. 0.05 / 1000 for every 3 years). 15, 17