Correspondence

Acute HIV Infection among Patients Tested for Mononucleosis

N Engl J Med 1999; 340:969March 25, 1999

Article

To the Editor:

Acute infection with human immunodeficiency virus type 1 (HIV-1) is associated with a self-limited, mononucleosis-like illness in the majority of persons. Symptoms may include fever, pharyngitis, lymphadenopathy, rash, oral and genital ulcerations, orthostasis, and gastrointestinal problems. Although many patients seek medical attention during acute HIV-1 infection, the diagnosis is often missed.1 In the early symptomatic stage, the standard enzyme-linked immunosorbent assay (ELISA) is negative for HIV-1, but tests for plasma HIV-1 RNA or plasma p24 antigen are positive. We hypothesized that health care providers are likely to perform testing for heterophil antibodies to Epstein–Barr virus in patients with the acute retroviral syndrome.

To test this hypothesis, we retrospectively performed quantitative HIV-1 RNA testing on serum collected for routine Epstein–Barr virus heterophil-antibody testing from 563 patients. Approval was obtained from the institutional review board to perform anonymous testing of all the heterophil-negative specimens from patients over 18 years of age. Serum specimens collected during a 12-month period were stored at –70°C before pooled testing with use of the Amplicor HIV Monitor test (Roche Diagnostic Systems). Each pooled sample consisted of 25 μl from eight different serum specimens. When viral RNA was detected, the eight specimens were tested individually.

Eleven of the 563 specimens (2.0 percent) were positive for HIV-1 RNA (Table 1Table 1Results of Testing in 11 Specimens Positive for HIV-1 RNA.). At least four of these (0.7 percent of the total) represented acute HIV-1 infection, with extremely high plasma levels of viral RNA but negative results on ELISA for HIV-1 and HIV type 2 (HIV-2). An additional 3 of the 11 patients (Patients 5, 6, and 7 in Table 1) had very high viral loads and positive results on ELISA for HIV-1 and HIV-2 and on assays for p24 antigen. These cases may represent acute HIV-1 retroviral syndrome with an early positive ELISA and a negative or evolving result on Western blot analysis. Unfortunately, there was not enough of each sample for us to perform Western blotting. The most liberal interpretation of these data is that 7 of the 563 patients (1.2 percent) who were tested for acute Epstein–Barr virus infection actually had primary HIV-1 infection. The other four patients listed in Table 1 as testing positive for HIV-1 RNA probably had chronic HIV-1 infection.

One limitation of this analysis is that we had no way to determine whether a patient was tested more than once, since all identifiers had been removed from the specimens. However, since the positive samples were obtained at widely separated times, it is likely that the four positive specimens and the three with results indicating possible acute infection were obtained from different patients. The number of viral copies detected may have been underestimated because we used serum samples rather than plasma.2

Given that about 1 percent of negative Epstein–Barr virus heterophil-antibody tests performed at our institution represent acute HIV-1 infection, we believe that health care providers who order such tests should perform an in-depth assessment of the patients' risk factors for HIV-1 and decide whether testing for acute HIV-1 infection is warranted.

Eric S. Rosenberg, M.D.
Angela M. Caliendo, M.D., Ph.D.
Bruce D. Walker, M.D.
Massachusetts General Hospital, Boston, MA 02114

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