Detection of Acute HIV Infection: We Can’t Close the Window

Acute human immunodeficiency virus (HIV) infection poses a dilemma for diagnosis, clinical management, and public health. It has been variously defined as the transient symptomatic illness associated with high-titer viral replication [1], the period from initial infection to complete seroconversion [2], and the phase between the appearance of detectable HIV RNA and detectable antibodies to HIV [3]. In the context of therapeutic trials, primary HIV infection includes the acute infection interval and the first 6 months after seroconversion, during which viral set point is established [4, 5]. ‘‘Detecting acute infection’’ has also been used synonymously with ‘‘closing the window,’’ the period during which tests for HIV are negative in persons who are infected. In this issue of the journal, Rosenberg et al [6] evaluated how well the Determine HIV-1/2 Ag/Ab Combo rapid test (Combo RT) compared with an algorithm of parallel antibody tests followed by RNA polymerase chain reaction. The Combo RT, designed for use at the point of care with finger-stick whole blood to detect HIV antibody and HIV antigen (and distinguish the two) in 20 minutes, did not fare very well in this comparison. The Combo RT is a lateral flow test (ie, an immunoassay that incorporates all necessary reagents into a single test strip). The test result is read visually, without instrumentation, after the specimen flows across the strip. Lateral flow tests have revolutionized HIV testing because they are easy to perform, require minimal training, have long-term stability, require no dedicated instrumentation, and can use whole blood specimens. In the United States, lateral flow HIV tests are used extensively in nonclinical settings. However, high hopes for point-of-care rapid tests able to identify acute infection, predicated on detecting p24 antigen, may be unrealistic. Recently developed fourthgeneration HIV antigen-antibody (Ag/Ab) combination assays, designed for use in the laboratory, detect both p24 antigen and antibodies against HIV but do not distinguish between the two. They exhibit an analytic sensitivity for p24 antigen of 11–18 pg/mL [7], equivalent to approximately 30 000–50 000 copies/mL of HIV RNA [8]. In contrast, lateral flow assays using colloidal gold have a lower limit of detection in the range of 1 ng/mL [9], 100-fold higher than the p24 antigen concentration usually present in plasma [8]. With the ultrasensitive procedure that includes heat dissociation of p24 antigen–antibody immune complexes, signal amplification, and instrumentation, the limit of detection for p24 (without additional pretreatment of the specimen to disrupt viral particles) can be $250 000 RNA copies/mL [10]. The findings of Rosenberg et al substantiate this: ultrasensitive methods were used to test 7 of the 8 acute specimens and failed to detect p24 antigen in 2 that had RNA concentrations of 45 000 and $750 000 copies/mL. In contrast, the ability of the Combo RT to establish the presence of antibodies to HIV was excellent. The Combo RT was positive for antibody in 162 (99.4%) of the 163 persons with established infection and in 2 of the 8 patients with acute HIV infection who were negative on other antibody tests. This latter finding suggests that the Combo RT might be able to identify many of the earliest infections. As shown in Table 1, antibody tests differ in their sensitivity to detect HIV during seroconversion [11]. Most lateral flow rapid tests in current use (and also Western blot analysis) are based on second-generation immunoassay principles that detect only immunoglobulin (Ig) G–class antibodies and become positive, on average, 20–25 days after RNA appears [12]. The antibody component of the Combo RT detects both IgMand IgGclass antibodies. Several studies suggest Received and accepted 9 November 2011; electronically published 29 December 2011. Correspondence: Bernard M. Branson, MD, CDC, 1600 Clifton Rd, MS D-21, Atlanta, GA 30333 (bbranson@cdc.gov). The Journal of Infectious Diseases 2012;205:521–4 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2011. DOI: 10.1093/infdis/jir793