39 HIV: primary infection

The period of time from the onset of infection until the immune system establishes a balance with viral replication. Characterized by rapidly increasing viraemia with transient immune suppression. Usually takes weeks–months to stabilize.

The symptomatic development of HIV-specific antibodies.

Difficult to determine because of the wide spectrum of clinical presentations which may be mild and non-specific (Table 39.1). These explain the wide range of reported prevalence of 30–93% in those recently infected. Clinician awareness, experience, and high index of suspicion ↑ diagnostic rate. It is unclear what determines the severity of symptoms. The inoculum size, HIV strain virulence, and patient’s immune status may be factors. Almost all reports of ARS are in adults with HIV-1, but it may occur in children or those with HIV-2 infection.

Symptoms usually begin 2–6 weeks after infection, typically lasting 5–10 days and rarely >14 days. Subjective symptoms such as fatigue may continue for several weeks or even months, but eventually almost all patients enter an asymptomatic phase that may last for years. Within 2–4 weeks of infection very high levels of free HIV and p24 antigen can be detected in the peripheral blood. Symptoms coincide with peak levels of plasma viraemia.

Fever followed by lymphadenopathy, pharyngitis, and skin rash.

Severe and prolonged illness, especially with neurological manifestations, is associated with a poorer prognosis. Resolution of symptoms coincides with ↓ in plasma viraemia and the development of a CD8 cell-specific immune response with the later emergence of HIV-specific antibodies (usually within 4–6 weeks of infection but may be up to 3 months).

More important than humoral immunity in containing HIV infection and develops earlier. HIV-specific immune responses, particularly cytotoxic CD8 cells, influence the natural history of HIV infection.

1° infection is characterized by active viral replication and very high levels of plasma viraemia. The virus disseminates throughout the body, particularly to the lymphoid system where its replication is never completely suppressed. During the first few days of infection both CD4 and CD8 cells are suppressed, resulting in lymphopenia approaching levels seen in patients with advanced disease. This is followed by relative lymphocytosis, predominantly CD8 cells, that declines when acute seroconversion is complete. However, the CD4 count, although increasing, does not return to baseline values. These changes result in reversal of the CD4/CD8 ratio to <1. One feature of acute HIV infection is the rapid depletion of CD4 cells in the gut lymphoid tissue which persists despite immune reconstitution with HAART.

HIV viraemia ↓ with HIV-specific immune responses, gradually stabilizing within 6–12 months to reach a ‘viral set-point’. Higher set-points indicate ↑ risk of disease progression.

Antibody response usually becomes detectable within 10–21 days of the onset of symptoms but may take up to 3 months from infection. Anti-bodies to gp160 and p24 develop first, followed by anti-gp120 and anti-gp41. Anti-p24 diminishes with time and may disappear with advanced disease. However, anti-gpl20 and anti-gp41 persist for life. Poor prognosis if inadequate HIV antibody response. Neutralizing antibodies are usually detected 4–8 weeks after resolution of the viraemic peak. Non-neutralizing antibodies to envelope and p24 antigens develop much earlier, coinciding with seroconversion.

PHI usually presents before the development of antibodies and therefore is diagnosed by finding p24 antigen or HIV RNA in the appropriate clinical setting. Fourth-generation HIV antibody tests also detect p24 antigen, and can test positive at the later stages of PHI but can be falsely negative. HIV RNA levels are usually extremely high, often >10⁶copies/mL.

Atypical lymphocytes are commonly seen in the peripheral blood with levels up to 30%. Anaemia, thrombocytopenia, abnormal liver function tests, or ↑ inflammatory markers may also be found (see Box 39.1 for differential diagnoses).

PHI is the time of highest infectivity in HIV infection. The plasma level of HIV RNA strongly predicts the progression rate. Early intervention has theoretical advantages as the virus is likely to be homogenous and the immune system intact. Antiretroviral treatment may ↓ the number of infected cells, preserve HIV-specific immune responses, and possibly ↓ the viral set-point. However, the long-term benefit of therapy has not been demonstrated.

It is unusual for PHI to be identified unless patients present with symptoms (ARS), the nature and severity of which may influence the decision to treat. If treatment is considered it is common practice to be offered entry into controlled clinical trials. Failing this, standard HAART may be given when CD4 is persistently low, or there is severe CNS disease or development of an AIDS-defining illness. Possible benefits of treatment should be weighed against drug toxicity, adherence, and potential for drug resistance in discussion with the patient. The optimum duration of treatment is not yet established. Benefit from structured treatment interruptions in stimulating host immune response has not been conclusively demonstrated. The role of drugs that inhibit activation of latently infected CD4 cells (e.g. hydroxycarbamide and ciclosporin A), with subsequent inability of virus production, is not known.

Other possible benefits of diagnosing PHI: