Q&A column

Editors: Olga Pozdnyakova, MD, PhD, Geoffrey Wool, MD, PhD, David Bernard, MD, PhD & Raul S. Gonzalez, MD

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Q. What is the recommended approach for determining the HIV status of patients who are taking HIV pre-exposure prophylaxis or have received oral PrEP within the past three months or intramuscular PrEP within the past 12 months?

A. July 2026—The CDC recommends a specific HIV testing algorithm for patients who are taking HIV PrEP or have taken an oral PrEP or PEP (post-exposure prophylaxis) within the past three months or injectable PrEP within the past 12 months because such patients are a distinct category as a result of their recent or ongoing intake of PrEP.

The rationale behind a specific testing algorithm is that an antiretroviral drug prophylaxis alters the dynamics of viral replication and the immune response, rendering nucleic acid-based assays and antigen-antibody detection assays less sensitive. Antiretroviral drugs may suppress the viral replication in a newly infected patient, leading to a low viral load. Low viremia may also be associated with suboptimal immune response, causing a false-negative result on an antibody-detection assay.

As a result, the CDC recommends performing an HIV-1 RNA assay and HIV antigen-antibody assay simultaneously. Positive results with both tests indicate HIV infection, whereas negative results for both tests indicate the absence of HIV infection. If the HIV-1 RNA assay is positive while the antigen-antibody assay is negative, or vice versa, HIV-1 RNA testing on a second blood specimen is recommended. Detection of HIV-1 RNA in the second blood specimen indicates HIV infection, and treatment should be initiated. Such HIV testing is recommended every two months for intramuscular PrEP and every three months for oral PrEP for timely detection of HIV infection that could result from medication nonadherence or, less likely, drug resistance. Prompt detection of HIV infection in such individuals is of utmost importance for initiating timely treatment of such infection.

A CAP Clinical Pathology Improvement Program case-based activity (available for purchase at https://bit.ly/CAP_CPIP-HIV) provides further information about laboratory diagnosis of HIV infection. Additional CPIP online activities are available at https://education.cap.org/casebased.

Sajjad Hassan, MD, D(ABMM)
Assistant Professor of Pathology
UMass Chan Medical School
Associate Director of Blood Banking/
Transfusion Medicine
Associate Director of Medical Microbiology
Director of Apheresis Medicine
Baystate Medical Center
Springfield, Mass.
Member, CAP Clinical Pathology
Education Committee

Q. Our providers pointed out that lipoprotein(a) results from different laboratories are discordant, so they asked us to bring the assay in-house. Is this a good idea?

A. Lipoprotein(a), or Lp(a), is a prothrombotic, proinflammatory, and atherogenic cholesterol-rich particle. Plasma concentration of Lp(a) is an important genetic determinant of atherosclerotic cardiovascular disease (ASCVD) risk, and new therapies targeting Lp(a) are progressing through clinical trials.^1–3 However, Lp(a) is not part of current standard lipid panels.

Lp(a) levels are hard to measure because differences in the amount of protein and lipid in each particle cause high variability in particle sizes within and among individuals. Like low-density lipoprotein, Lp(a) contains one apolipoprotein B-100 protein molecule, but it also carries a molecule of apolipoprotein (a) (apo[a]). Variation in the LPA gene that encodes apo(a) leads to a variable number of kringle IV type 2 (KIV-2) repeats and a broad range of apo(a) isoforms.⁴ Different LPA alleles lead to different sizes of apo(a) protein, and differences in lipid metabolism lead to varying amounts of cholesterol, triglycerides, and phospholipids in each Lp(a) particle. When combined, these differences cause significant variability in Lp(a) mass within and among patients.

Assays that use antibodies against the variable KIV-2 domain over- or underestimate the amount of Lp(a) when a patient’s apo(a) isoforms contain a high or low number of KIV-2 repeats, respectively.^4,5 To further complicate the interpretation of Lp(a) assays, the term Lp(a) mass is ambiguous because samples with the same Lp(a) mass may contain different molar concentrations of Lp(a) particles since the particle size and mass vary based on heterogeneous Lp(a) isoforms.⁴ It is clear that patients with a high molar concentration of Lp(a) particles—a more accurate measure of atherogenic particle burden than KIV-2-dependent mass—have an increased risk of ASCVD and aortic valve stenosis.⁶ Yet the molecular heterogeneity of Lp(a) and the fact that reagent antibodies often recognize the variable KIV-2 domain of apo(a) have led to the development of immunoassays that do not agree with one another.

Multiple medical societies have issued joint guidelines on Lp(a) testing, including the following. All adults should undergo testing for Lp(a) at least once.⁷ Values greater than 75 nmol/L indicate increased ASCVD risk, with values greater than 250 nmol/L associated with a twofold or greater estimated risk.⁸ Mass-based units should be considered approximate for clinical decision-making given the heterogeneity of Lp(a) particle mass.^5,7 The standardization of assays that report the molar concentration of Lp(a) is, therefore, essential.

There are several important steps in standardizing Lp(a) testing. Lp(a) values should be assigned by a method validated to be independent of apo(a) isoforms and should be reported in nanomoles per liter. Values in mass units should not be converted to nmol/L due to variability in particle mass and lack of a standard conversion factor.^5,8 Assays should also be calibrated in a manner traceable to reference materials that span a clinically meaningful range of 75 to greater than 200 nmol/L to reflect commonly used clinical decision thresholds for ASCVD. (Of note, this range may not be appropriate for all populations.)

Building on prior standardization efforts, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) is replenishing reference materials for Lp(a) testing.^5,9,10 In the interim, the CDC Lipid Standardization Program is offering a phase one kit consisting of samples tested by the IFCC mass spectrometry method and spanning concentration and KIV-2 size ranges.

Lp(a) testing will become increasingly important as new targeted therapies enter clinical practice. An in-house assay can deliver internally consistent, traceable results, but discordance with outside laboratories will persist until the field fully adopts isoform-independent, standardized methods. Laboratory directors considering insourcing should confirm that candidate assays meet both criteria—isoform independence and traceability to reference materials—and review CAP proficiency testing performance and other Survey data before implementing such assays.

1. Emerging Risk Factors Collaboration. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–423.
2. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361(26):2518–2528.
3. De Los Reyes C, Rikhi RR, Doherty S, et al. Current clinical trials for treating elevated lipoprotein(a). Curr Cardiovasc Risk Rep. 2025;19(1):7. doi.org/10.1007/s12170-025-00759-8
4. Marcovina SM, Albers JJ, Gabel B, Koschinsky ML, Gaur VP. Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a). Clin Chem. 1995;41(2):246–255.
5. Cobbaert CM, van Neer NJM, Diederiks NM, Leijnse EJJ, Ruhaak LR. On the cusp of global lipoprotein(a) standardization. Clin Chem Lab Med. 2026;64(5):1064–1073.
6. Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes. J Am Coll Cardiol. 2019;74(24):2982–2994.
7. Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of dyslipidemia: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026;153(17):e1154–e1276.
8. Kronenberg F, Moira S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925–3946.
9. Tate JR, Berg K, Couderc R, et al. International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Standardization Project for the Measurement of Lipoprotein(a). Phase 2: selection and properties of a proposed secondary reference material for lipoprotein(a). Clin Chem Lab Med. 1999;37(10):949–958.
10. Dati F, Tate JR, Marcovina SM, Steinmetz A. First WHO/IFCC international reference reagent for lipoprotein(a) for immunoassay—Lp(a) SRM 2B. Clin Chem Lab Med. 2004;42(6):670–676.

Sridevi Devaraj, PhD, DABCC
Medical Director, Clinical Chemistry and Point of Care Testing
Texas Children’s Hospital and
Pavilion for Women
Director of Laboratories
Center for Women and Children
Texas Children’s Health Plan
Professor of Pathology and Immunology
Baylor College of Medicine
Houston, Tex.
Member, CAP Accuracy-Based
Programs Committee

Andrew Hoofnagle, MD, PhD
Professor of Laboratory
Medicine and Pathology
Head, Division of Clinical Chemistry
Department of Laboratory
Medicine and Pathology
University of Washington
Seattle, Wash.
Chair, CAP Accuracy-Based
Programs Committee

Brian L. Harry, MD, PhD
Clinical Assistant Professor of Pathology
Co-Director, Internal Operations,
Michigan Medicine Laboratories
University of Michigan
Ann Arbor, Mich.
Member, CAP Accuracy-Based
Programs Committee