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The clinical spectrum of the acute retroviral syndrome of primary HIV-1 infection is the result of the initial penetration and widespread dissemination of the HIV virus. The illness is often referred to as an HIV-mononucleosis or glandular feverlike disorder. Table 83-1 lists some of the protean signs and symptoms manifested during primary HIV infection. The acute clinical response to HIV-2 infection is similar to the clinical illness associated with primary HIV-1 infection. Some of the distinguishing features of primary HIV infection are an exanthem (macular or maculopapular oval or rounded lesions) with a predilection for the upper thorax, face, and forehead and oral-genital-anal ulcers. The most common manifestations include fever, fatigue, pharyngitis, myalgias, and headache. When symptoms and signs do develop (estimated to occur in 50% to 70% of infected patients), they appear after an incubation period of 11 days to 6 weeks. Clinical manifestations usually resolve spontaneously within 1 to 4 weeks (average duration, 25 days), although resolution occasionally requires more than 40 days. On occasion, concomitant AIDS-defining disorders develop, such as Pneumocystis carinii pneumonia, miliary tuberculosis, tuberculous meningitis, candidal esophagitis, cyto-megalovirus (CMV) pneumonitis, CMV colitis, CMV encephalitis, ocular cryptococcosis, and prolonged cryptosporidiosis, so that when a symptom complex is unusual in severity and/or duration for primary HIV infection, the possible presence of a coexistent, treatable infecting agent needs to be considered. Rarely, it is difficult to determine if the patient has acute primary HIV infection with severe immunosuppression or advanced AIDS with the inability to demonstrate antibody.

Table 83-1. Abnormal signs and symptoms described in patients with primary HIV infection

Lymphadenopathy occurs commonly, appearing in the second week of illness, and most often involves the axillary, occipital, and cervical nodes. The adenopathy persists following the acute illness, but the size of affected nodes tends to decrease with time.

Laboratory findings include (initially) a reduction of total lymphocyte and T-cell subset counts, followed (by the beginning of the second week) by an increase in the concentration of CD8 cells and an inversion of the ratio of CD4 to CD8 cells. These latter findings can be accompanied by thrombocytopenia and, less commonly, atypical lymphocytes. Virus has been recovered from seminal fluid, peripheral blood (mononuclear cells and plasma), cerebrospinal fluid (often with a lymphocytic elevation), and bone marrow.
A number of studies have noted an association between specific features of symp-tomatic primary HIV infection, such as persistent fever and neurologic manifestations (encephalitis, meningitis, neuritis), peak plasma levels of HIV-1 RNA (determined more than 120 days after onset of disease), and accelerated progression of disease to AIDS and death.
The traditional screening test, the enzyme-linked immunosorbent assay (ELISA), may not detect antibodies to HIV for 1 to 2 months or even longer after development of disease, and rarely, the lack of antibody formation persists well beyond the expected “window” period. The diagnosis of primary HIV infection during the period of high viral replication in the absence of detectable antibody (“window of infectivity” period) has been established by the detection of p24 antigen. However, the detection of HIV RNA in plasma is a more sensitive test than the detection of p24 antigen, and this test can detect primary infection 3 to 5 days earlier. Culture of HIV from peripheral blood mononuclear cells is also a more sensitive test than detection of p24 antigen.
The diverse manifestations of primary HIV infection can resemble those of numerous other conditions, including drug reaction, Epstein-Barr virus (EBV) infection, influenza, CMV infection, rubella, parvovirus infection, hepatitis B, syphilis, toxoplasmosis, Lyme disease, leptospirosis, “aseptic” meningitis, and herpes encephalitis. The presence of a skin rash (rare in EBV infection unless the patient has received an antimicrobial), mucocutaneous ulcers, diarrhea, and cough suggest primary HIV infection rather than EBV infection. Pharyngeal exudate, lymphadenopathy, atypical lymphocytes, and abnormal levels of liver enzymes are noted in both these viral infections.
When patients manifest signs and symptoms compatible with acute HIV infection, a quantitative determination of viral load should be performed. If this “early” laboratory test demonstrates evidence of HIV (which should be confirmed in 6 weeks with the ELISA and Western blot antibody tests because false-positive HIVRNA tests have been reported), patients should be counseled regarding their disease. Patients must also be informed about the spread of HIV and the need to notify persons for whom they may have been a source of high-risk exposure (vaginal, rectal, oral-genital sex; sharing of needles, syringes) and be made aware of the various treatment options (no therapy; referral to a specialist at an AIDS center; monotherapy or combination antiretroviral treatments).
Zidovudine monotherapy during acute primary infection has resulted in increased CD4-cell counts and reduced development of “minor” opportunistic infections (oral candidiasis, oral hairy leukoplakia, herpes zoster). However, because patients with primary infection may harbor zidovudine-resistant strains of HIV, because acute curtailment of viral production helps the immune system to clear virus (resulting in a lower viral “set point”), and because combination treatments have the capacity to exert a potent antiviral effect (reduce virus in peripheral blood, peripheral lymph nodes, and gastrointestinal lymphoid tissue), some experts recommend that patients receive triple therapy with compounds that affect different parts of the viral life cycle. Certainly, therapy (consisting of two nucleoside analog reverse transcriptase inhibitors plus a protease inhibitor) should be recommended to patients with plasma RNA concentrations greater than 5,000 copies per milliliter regardless of the CD4-cell count. Patients must be counseled regarding their willingness to commit themselves to this costly, complex, and potentially toxic regimen. For those patients who cannot tolerate or comply with the three-drug regimen containing a protease inhibitor, the recommended alternative treatment consists of two nucleoside analog reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor (nevirapine, delavirdine or efavirenz). The drugs should be prescribed for at least 6 months (perhaps indefinitely) and be initiated simultaneously, not in sequence. Unfortunately, however, there is a paucity of clinical trial data to guide the clinician. (R.A.G.)
Berger DS, et al. Acute primary human immunodeficiency virus type 1 infection in a patient with concomitant cytomegalovirus encephalitis. Clin Infect Dis 1996;23:66–70.
Primary HIV infection can occur with a coexistent opportunistic infection that normally develops in a patient with profound immunosuppression (AIDS).
Boufassa F, et al. Influence of neurologic manifestations of primary human immunodeficiency virus infection on disease progression. J Infect Dis 1995;171:1190–1195.
Neurologic manifestations of primary HIV infection are associated with an accelerated progression of disease.
Centers for Disease Control. Persistent lack of detectable HIV-1 antibody in a person with HIV infection—Utah 1995. MMWR Morb Mortal Wkly Rep 1996;45:181–185.
A patient with confirmed HIV infection in whom results of enzyme immunoassays for HIV antibody were persistently negative beyond the expected “window period.”
Kahn JO, Walker BD. Acute human immunodeficiency virus type 1 infection. N Engl J Med 1998;339:33–39.
A contemporary assessment of primary HIV infection.
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Antiretroviral therapy administered during primary infection may improve the subsequent clinical course and increase the CD4-cell count.
Lafeuillade A, et al. Effects of a combination of zidovudine, didanosine, and lamivudine on primary human immunodeficiency virus type 1 infection. J Infect Dis 1997; 175:1051–1055.
Triple-drug therapy has a potent antiviral effect during primary HIV-1 infection.
Lapins J, et al. Mucocutaneous manifestations in 22 consecutive cases of primary HIV-1 infection. Br J Dermatol 1996;134:257–261.
A review of the mucocutaneous manifestations of primary HIV-1 infection.
Nui MT, et al., DATRI 002 Study Group. Zidovudine treatment in patients with primary (acute) human immunodeficiency virus type 1 infection: a randomized, double-blind, placebo-controlled trial. J Infect Dis 1998;178:80–91.
An example of clinical studies designed to assess the merits of drug treatment of primary HIV.
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A review of the clinical spectrum, diagnosis, and treatment.
Schacker T, et al. Clinical and epidemiologic features of primary HIV infection. Ann Intern Med 1996;125:257–264.
Detection of HIV RNA in plasma is more sensitive than p24 antigenemia to test for HIV seroconversion.
Schacker TW, et al. Biological and virologic characteristics of primary HIV infection. Ann Intern Med 1998;128:613–620.
Peak plasma HIV-1 RNA levels in the first 120 days were not predictive of disease progression.
Vanhems P, et al. Acute human immunodeficiency virus type 1 disease as a mononucleosis-like illness: is the diagnosis too restrictive? Clin Infect Dis 1997;24:965–970.
The mean duration of primary HIV infection is 25 days, and the most common abnormalities are fever, lethargy, rash, myalgia, and headache.
Vanhems P, et al. Severity and prognosis of acute human immunodeficiency virus type 1 illness: a dose-response relationship. Clin Infect Dis 1998;26:323–329.
Clinical expression of disease correlates with rate of progress.
Veugelers PJ, et al. Incidence and prognostic significance of symptomatic primary human immunodeficiency virus type 1 infection in homosexual men. J Infect Dis 1997;176:112–117.
Fever is associated with faster disease progression.


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