What is the most important next step for a 25-year-old man with a one-week history of sore throat, cervical tender adenopathy, arthralgia, and rash, who has a recent history of treated syphilis, negative heterophile antibody test, and abnormal lab results including leukopenia (low white blood cell count) with lymphocytosis (high lymphocyte count)?

Acute HIV Infection Testing

The most important next step is to obtain an HIV RNA (viral load) test or 4th generation HIV antigen/antibody test to evaluate for acute HIV infection, as the clinical presentation is highly suggestive of acute retroviral syndrome despite the negative initial HIV antibody test.

Clinical Reasoning

This patient presents with a classic constellation of findings for acute HIV infection (acute retroviral syndrome):

• Mononucleosis-like syndrome with sore throat, fever, lymphadenopathy, and rash occurring 2-4 weeks after potential exposure 1
• Characteristic rash in the cervical and axillary distribution (macular rash in typical locations for acute HIV) 1
• Oral ulcers (mucocutaneous lesions common in acute HIV) 1
• Leukopenia with lymphocytosis (WBC 3.8 with 80% lymphocytes) - this pattern is atypical for typical infectious mononucleosis and more consistent with acute HIV 2
• Negative heterophile antibody ruling out EBV infectious mononucleosis 3, 4
• Recent STI history (treated syphilis 2 weeks ago) indicating high-risk sexual behavior 1

Why Standard HIV Testing May Be Negative

The initial HIV test was negative, but this does not exclude acute HIV infection:

• Antibody tests can be falsely negative during the "window period" of acute HIV infection, which typically lasts 2-4 weeks after exposure 2
• Acute HIV can mimic secondary syphilis with constitutional symptoms and CSF abnormalities, creating diagnostic confusion 1
• HIV RNA becomes detectable 10-14 days before antibody tests turn positive 2

Diagnostic Approach

Immediate Testing Required:

• HIV RNA (viral load) testing - detects virus during the window period before antibodies develop 2
• 4th generation HIV antigen/antibody test - detects both p24 antigen (present in acute infection) and antibodies 2

Additional Considerations:

• Repeat syphilis serology to ensure adequate treatment response, as HIV coinfection can cause atypical serologic responses 2
• Consider CSF examination if neurologic symptoms develop, as both acute HIV and neurosyphilis can present with CNS involvement 2

Critical Pitfalls to Avoid

• Do not rely on negative antibody-only HIV tests in patients with acute retroviral syndrome - the window period can lead to false reassurance 2
• Do not dismiss the diagnosis based on recent syphilis treatment - HIV and syphilis frequently coexist, and the CDC recommends all syphilis patients be tested for HIV 1
• Do not assume EBV mononucleosis when heterophile is negative and the clinical picture fits acute HIV better 3, 4
• Recognize that leukopenia with lymphocytosis is more consistent with acute HIV than with typical EBV mononucleosis, which usually causes lymphocytosis without leukopenia 4, 5

Management Pending Results

While awaiting HIV RNA results:

• Counsel the patient about the possibility of acute HIV infection and the importance of follow-up 2
• Advise against sexual contact until diagnosis is clarified, as viral loads are extremely high during acute infection 6
• Arrange urgent follow-up within 48-72 hours to review results and initiate antiretroviral therapy if positive 2