Initial Evaluation

Case 1: Discussion

Clinical Manifestations

In the United States, more than 50,000 persons are newly infected with HIV each year and an estimated 40-90% of these individuals will have an acute symptomatic illness that typically has its onset within 28 days from the time of the HIV infection[1,2]. Patients with symptomatic acute (primary) HIV infection characteristically deve lop a mononucleosis-like illness with multiple, non-specific systemic symptoms, including fever, lethargy, myalgias, rash, lymphadenopathy, and headache (Figure 1)[1,2,3,4]. When rash is present, it usually appears as a morbilliform or maculopapular rash, more prominent centrally than peripherally (Figure 2). Less common manifestations include acute meningoencephalitis[5], facial palsy, Guillain-Barré, oral ulcers, genital ulcers, and splenomegaly. Although some of the common clinical manifestations may suggest a diagnosis of acute HIV, the overall features of the clinical illness associated with acute HIV infection are not highly sensitive or specific (Figure 3)[4,6,7]. Overall, most cases of acute HIV infection go undiagnosed or are misdiagnosed[2], especially if the history of recent exposure to HIV is not obtained. The duration of the acute retroviral syndrome is usually 3 to 14 days[2]. Several groups of investigators have shown that patients who develop more severe and prolonged symptoms are likely to have a more rapid progression of their HIV disease[8,9,10].

Differential Diagnosis

The differential diagnosis of patients presenting with acute HIV includes mononucleosis, secondary syphilis, acute cytomegalovirus infection, acute toxoplasmosis, acute hepatitis B virus infection, and enterovirus infection. Rarely, persons with acute HIV infection may have a marked decline in their CD4 cell count and develop an opportunistic infection, such as oral candidiasis or Pneumocystis pneumonia[2]. Routine laboratory studies taken from persons acutely infected with HIV may show leucopenia, thrombocytopenia, and increases in hepatic transaminases levels. Atypical lymphocytes are not generally seen.

Immunopathogenesis

The immunopathogenesis of acute HIV infection is best understood with regard to transmission via the genital mucosa. Studies of intravaginal inoculation of simian immunodeficiency virus (SIV) in rhesus monkeys[11]have helped to generate a model for the early events of human sexual transmission of HIV (Figure 4)[1]. The current model for human HIV infection of the genital mucosa suggests that Langerhans cells (tissue dendritic cells located just below the mucosa) are the first cells to be infected. The virus first binds to the CD4 molecule on susceptible cells, followed by binding to the cellular coreceptor. The Langerhans cells express CCR5 coreceptors, but usually not CXCR4 coreceptors. Most often, the transmitted HIV is macrophage-tropic HIV (also known as R5 HIV) and this virus preferentially binds to the CCR5 coreceptor, as opposed to the CXCR4 coreceptor. The dendritic cells provide an efficient means for HIV to reach the T-cell lymphocytes within lymph nodes. Human tissues studies have shown these dendritic cells cluster and preferentially infect memory CD4 cells (as opposed to naive CD4 cells)[12]. Once the infected dendritic cells reach the lymph nodes, they fuse with CD4 cells and spread the HIV to deeper tissues. In animal studies, SIV is detected in the internal iliac lymph nodes within 2 days after infection[11]. Investigators have shown that humans typically develop HIV viremia within 4-11 days of initial transmission[13]. In this acute phase, newly infected persons have high levels of HIV in the genital tract and are thus considered highly infectious[1]. The uncontrolled initial burst of viremia typically corresponds with very high plasma HIV RNA levels, often greater than 100,000 copies/ml. Although antibody responses against HIV are generated, the initial neutralizing antibodies have weak neutralizing activity against primary HIV isolates and thus probably contribute very little to the initial control of HIV [14]. The initial burst of viremia is followed by a decrease in HIV RNA levels, predominantly as a result of a potent CD8 cytotoxic lymphocyte response targeted against HIV[14,15]. The HIV RNA levels reach a steady state, or so called set point, by 6 months after infection and, if untreated, remain at a similar level for years thereafter[16]. Investigators have shown that individuals have qualitatively different immune responses to primary HIV infection[17]. It appears that persons with strong initial cytotoxic T-lymphocyte responses have lower HIV RNA levels after 6 to 12 months, and subsequently experience a slower progression of their HIV disease (Figure 5)[17,18,19]. The initial HIV RNA level obtained with primary HIV infection, however, does not appear to have predictive value for progression of disease[17].

Laboratory Diagnosis

Patients who present with initial symptoms of acute HIV infection typically have a very high HIV RNA level and a negative HIV antibody test (Figure 6). The laboratory diagnosis of acute HIV requires a negativ (or indeterminate) HIV antibody assay plus either a high HIV RNA level or a positive p24 antigen test. In one study that involved 436 patients who had symptoms consistent with acute retroviral syndrome, the p24 antigen test showed a sensitivity of 89% and specificity of 100% whereas the HIV RNA assay had a sensitivity of 100% and specificity of 97%[4]. True positive HIV RNA results were consistently greater than 100,000 copies/ml whereas false-positive tests were seen with HIV RNA levels less than 10,000 copies/ml[4,20]. Potential explanations for fals positive HIV RNA results include laboratory error, cross-contamination within the laboratory, and mix-up of specimens or test results[20]. Those patients with suspected false-positive HIV RNA levels need close follow-up that includes repeat HIV antibody tests and repeat HIV RNA levels. The greater sensitivity of the HIV RNA assay compared with the p24 antigen assay predominantly occurs because the HIV RNA assay detects HIV 3 to 7 days earlier than the p24 antigen assay[1,4,21]. Serologic tests first turn positive at approximately 3-6 weeks after acquisition of HIV, with IgM-sensitive enzyme immunoassays (EIAs) typically turning positive at about 3-4 weeks. Most patients have a window period (positive HIV RNA and negative HIV antibody) of approximately 3 weeks[21]. Western blot testing initially shows an indeterminate pattern (presence of HIV specific bands that fail to meet criteria established by US FDA for positive HIV as reactivity to two of the following three bands: p24, gp41, gp120/160). In addition, the presence of a positive Western blot without reactivity to p31 (pol) suggests antibody seroconversion within the preceding 2 to 3 months[21]. In addition, a modified less sensitive HIV EIA test, the so-called "detuned" assay, can differentiate those with recent HIV infection (acquired HIV within the previous 4-5 months) from those with well-established chronic HIV infection[22]; this test can be particularly useful for those with recent infection who have already passed through the window period. One group of investigators has generated a model that divides acute HIV into 6 stages based on the timing of diagnostic tests (Figure 7). The characteristic formation of antibodies may be altered in patients with acute HIV infection who receive antiretroviral therapy (and have durable virologic suppression); in this scenario, patients may have incomplete evolution of antibody responses and rarely will show a complete or partial seroreversion.

Treatment

The initiation of antiretroviral therapy in persons newly infected with HIV infection remains highly controversial. This topic, as well as resistance testing for persons newly infected with HIV are discussed in detail in Case 4 in the Antiretroviral Rx section.