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HIV-1/2 Antigen and Antibodies, Fourth Generation, With Reflexes

Test code: 91431

No. The HIV antigen/antibody assay listed above detects HIV antibodies that could be passively transferred from infected mothers to their infants.1,2 Quest Diagnostics offers the following nucleic acid tests that are appropriate for infants below the age of 2 years:

  • HIV-1 and HIV-2 RNA, Qualitative PCR (test code 14312)
  • HIV-1 DNA, Qualitative, PCR (test code 8401)

Recommendations for HIV screening include the following3-5:

  • All persons aged 15 to 65 years encountered in all healthcare settings3
  • Persons seeking treatment for sexually transmitted infections
  • Younger adolescents and older adults who are at increased risk of infection
  • All pregnant persons, including those who present in labor or at delivery, whose HIV status is unknown
  • Persons engaging in high-risk behaviors associated with HIV acquisition (should be screened at least annually)

Opt-out HIV screening (notifying the patient that an HIV test will be performed, unless the patient declines) is recommended in all healthcare settings.

A study using a variety of HIV-1 seroconversion sample panels in conjunction with statistical modeling estimated that half of patients become repeatedly reactive on fourth-generation testing within 18 days after HIV infection; more than 99% have reactive results within 45 days after HIV acquisition. Therefore, HIV infection is very unlikely (ie, less than 1%) in patients with negative fourth-generation test results at least 45 days after the most recent exposure.6

Yes, the reflex pathway (Figure) for test code 91431 (HIV-1/2 Antigen and Antibodies, Fourth Generation, With Reflexes) is compliant with the 2023 updated CDC testing algorithm.7

The precise reason for a biological false-positive result in any individual specimen is not likely to be definitively identified. A few of the causes hypothesized in the medical literature include recent administration of certain vaccines, presence of HLA-DR antibodies, presence of rheumatoid factors, reactive rapid plasma reagin (RPR), hypergammaglobulinemia, cross-reactive immune response to other exogenous and endogenous retroviruses, recent SARS-CoV-2 infection,8 cancer,9 and autoimmune conditions.

There are occasional biological false-positive results with HIV screening tests, although the specificities of the FDA-approved HIV screening tests are very high (>99%). The potential adverse effects of a biological false-positive screening test result are ameliorated by use of the CDC-recommended multi-step testing algorithm. Test results are only considered to support the diagnosis of HIV infection when the screening test results are repeatedly reactive and either supplemental test (ie, HIV-1/2 antibody differentiation or HIV-1/2 RNA) is positive.5

A  retrospective study screened nearly 45,000 pregnant women with a fourth-generation HIV test to determine whether there was a difference in false-positivity rate before the COVID-19 pandemic versus after.10 In this study, a higher false-positive rate was observed for pregnant women after the start of the pandemic (0.32% after versus 0.19% before) due to COVID-19 infection during the pregnancy. Nonetheless, the false-positive rates in pregnant women were relatively low.

A fourth-generation test that is repeatedly reactive with HIV-1/2 antibody and RNA negative results is interpreted as HIV negative. Follow-up testing is generally not recommended. Additional testing is only indicated if the patient is thought to be very recently infected and/or the patient is at continued risk for HIV exposure. Refer to the HIV resource page on cdc.gov for updated recommendations.11

References

  1. US Department of Health and Human Services. HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV—A Working Group of the Office of AIDS Research Advisory Council (OARAC). Guidelines for the use of antiretroviral agents in pediatric HIV infection [pages C-1 to C-6]. In: ClinicalInfo.HIV.gov [Internet]. Rockville (MD). Updated December 19, 2024. Accessed March 25, 2025. https://www.ncbi.nlm.nih.gov/books/NBK586303/
  2. Siberry GK. Preventing and managing HIV infection in infants, children, and adolescents in the United States. Pediatr Rev. 2014;35(7):268-286. doi: 10.1542/pir.35-7-268
  3. US Preventive Services Task Force. Screening for HIV Infection: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;321(23):2326–2336. doi:10.1001/jama.2019.6587
  4. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR Recomm Rep. 2006;55(RR-14):1-17. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5514a1.htm
  5. Workowski KA, Bachmann LH, Chan PA, et al. CDC Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1-187. Accessed March 27, 2025. https://www.cdc.gov/mmwr/volumes/70/rr/rr7004a1.htm
  6. Delaney KP, Hanson DL, Masciotra S, et al. Time until emergence of HIV test reactivity following infection with HIV-1: implications for interpreting test results and retesting after exposure. Clin Infect Dis. 2017;64:53-59. doi: 10.1093/cid/ciw666
  7. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (US). Division of HIV/AIDS Prevention: Association of Public Health Laboratories (US). Technical update for HIV nucleic acid tests approved for diagnostic purposes. Published May 16, 2023. Accessed March 18, 2025. https://stacks.cdc.gov/view/cdc/129018
  8. Gudipati S, Shallal A, Peterson E, et al. Increase in false-positive fourth-generation human immunodeficiency virus tests in patients with coronavirus disease 2019. Clin Infect Dis. 2023;77(4):615–619. doi:10.1093/cid/ciad264
  9. Chiu C-Y, Mustafayev K, Bhatti MM, et al. False-reactive fourth-generation human immunodeficiency virus testing in cancer patients. Clin Infect Dis. 2024;78(3):674-680. doi:10.1093/cid/ciad608
  10. Miller ME, Cevigney R, Ayyash M, et al. Higher rates of false-positive HIV antigen/ antibody screens during the COVID-19 pandemic: implications for pregnant patients. Am J Obstet Gynecol. 2023;228(1):S690. https://doi.org/ 10.1016/j.ajog.2022.11.1156
  11. Centers for Disease Control and Prevention (CDC) HIV Nexus: CDC Resources for Clinicians. Clinical Testing Guidance for HIV. February 10, 2025. Accessed March 26, 2025. https://www.cdc.gov/hivnexus/hcp/diagnosis-testing/index.html

 

This FAQ is provided for informational purposes only and is not intended as medical advice. A physician’s test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

 

Document FAQS.106 Version: 5

Version 4 effective to 06/23/2025 to present          

Version 3 effective 07/10/2017 to 06/23/2025

Version 2 effective 01/13/2016 to 07/10/2017

Version 1 effective 08/15/2014 to 01/12/2016

Version 0 effective 08/08/2013 to 08/14/2014



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