Marcus Altfeld and Bruce D. Walker

Acute HIV-1 infection presents in 40 - 90 % of cases as a transient symptomatic illness, associated with high levels of HIV-1 replication and an expansive virus-specific immune response. With 14,000 new cases per day worldwide, it is an important differential diagnosis in cases of fever of unknown origin, maculopapular rash and lymphadenopathy.

The diagnosis of acute infection is missed in the majority of cases, as other viral illnesses ("flu") are often assumed to be the cause of the symptoms, and there are no HIV-1-specific antibodies detectable at this early stage of infection. The diagnosis therefore requires a high degree of clinical suspicion, based on clinical symptoms and history of exposure, in addition to specific laboratory tests (detection of HIV-1 RNA or p24 antigen and negative HIV-1 antibodies) confirming the diagnosis.

An accurate early diagnosis of acute HIV-1 infection is important, as patients may benefit from therapy at this early stage of infection (see below), and infection of sexual partners can be prevented.

After an incubation period of a few days to a few weeks, most cases present with an acute flu-like illness. The most common symptoms (see Table 1) are fever, maculopapular rash, oral ulcers, lymphadenopathy, arthralgia, pharyngitis, malaise, weight loss, aseptic meningitis and myalgia. In a recently published study by Hecht et al., fever (80 %) and malaise (68 %) had the highest sensitivity for clinical diagnosis of acute HIV-1 infection, whereas loss of weight (86 %) and oral ulcers (85 %) had the highest specificity. In this study, the symptoms of fever and rash (especially in combination), followed by oral ulcers and pharyngitis had the highest positive predictive value for diagnosis of acute HIV-1 infection. In another study by Daar et al., fever, rash, myalgia, arthralgia and night sweats were the best predictors for acute HIV-1 infection.

The symptomatic phase of acute HIV-1 infection lasts between 7 - 10 days, and rarely longer than 14 days. The severity and duration of symptoms has prognostic implications, as severe and prolonged symptoms are associated with more rapid disease progression. The nonspecific nature of the symptoms poses a great challenge to the clinician and underlines the importance of a detailed history of exposure.

The diagnosis of acute HIV-1 infection is based on the detection of HIV-1 replication in the absence of HIV-1 antibodies, as these are not yet present at this early stage of infection. Different tests are available for diagnosis of acute HIV-1 infection. The most sensitive tests are based on detection of plasma HIV-1 RNA.

In a recently published study, all assays for HIV-1 RNA that were tested (branched chain DNA, PCR and GenProbe) had a sensitivity of 100 %, but occasionally (in 2 - 5 % of cases) led to false positive results. False positive results from these tests are usually below 2,000 copies HIV-1 RNA per ml plasma, and therefore far below the high titers of viral load normally seen during acute HIV-1 infection (in our own studies on average 13 x 10⁶ copies HIV-1 RNA/ml with a range of 0.25 - 95.5 x 10⁶ copies HIV-1 RNA/ml). Repetition of the assay for HIV-1 RNA from the same sample with the same test led to a negative result in all false positive cases. Measurement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of 100 % with 100 % specificity. In contrast, detection of p24 antigen has a sensitivity of only 79 % with a specificity of 99.5 - 99.96 %. The diagnosis of acute HVI-1 infection must be subsequently confirmed with a positive HIV-1 antibody test (seroconversion) within the following weeks.

During acute HIV-1 infection, there is frequently a marked decrease of CD4+ cell count, which later increases again, but usually does not normalize to the initial levels. In contrast, the CD8+ cell count rises initially, which may result in a CD4+/CD8+ ratio of < 1. Infectious mononucleosis is the most important differential diagnosis. Hepatitis, influenza, toxoplasmosis, syphilis and side effects of medications may also be considered.

The goal of antiretroviral therapy during acute HIV-1 infection is to reduce the number of infected cells, preserve HIV-1-specific immune responses and possibly lower the viral set point in the long term. Several studies in recent years have shown that treatment of acute HIV-1 infection allows long-term viral suppression, leads to preservation and even increase of HIV-1-specific T helper cell responses and allows for the conservation of a very homogeneous virus population.

First pilot studies in patients who were treated during acute HIV-1 infection and subsequently went through structured treatment interruptions show that the HIV-1-specific immune response could be boosted in these patients. Most patients were subsequently able to discontinue therapy and experienced at least temporal control of viral replication, with viral set points remaining below 5,000 copies/ml for more than 3 years in some patients. However, in a number of individuals viral load rebounded to higher level during longer follow-up, requiring the initiation of therapy.

The long-term clinical benefit of early initiation of therapy has not been demonstrated yet. It is also not known how long the period between acute infection and initiation of therapy can be without losing immunological, virological and clinical benefit. In view of all these unanswered questions, patients with acute HIV-1 infection should be treated in controlled clinical trials. If this is not possible, the option of standard first-line treatment should be offered and discussed. Usually, treatment continues for at least a year, followed by structured treatment interruptions within the framework of controlled studies. It is important during counseling to clearly indicate the lack of definitive data on clinical benefit and to address the risks of antiretroviral therapy and treatment interruptions, including drug toxicity, development of resistance, acute retroviral syndrome during viral rebound and HIV-1 transmission and superinfection during treatment interruptions.

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