Primary HIV-1 infection: a new medical emergency?

Recognition of this initial illness may permit early diagnosis and treatment

Patients with HIV-1 infection are usually not diagnosed until they present with an opportunistic infection, often several years after their initial seroconversion. Increasingly, however, it is recognised that many people suffer an acute mononucleosis-like illness shortly after seroconversion. Despite the protean manifestations of this initial infection, primary HIV-1 infection is now recognisable as a distinct clinical entity. The clinical findings are associated with the immune response to the rapid dissemination of HIV throughout the body and may represent an important early opportunity for diagnosis and intervention.

Primary HIV-1 infection has been described as a “mononucleosis-like illness of acute onset occurring 2-6 weeks after HIV-1 infection, usually resolving after 1-2 weeks, though occasionally lasting considerably longer.”1 2 It has been estimated that 53-93% of gay men who have recently acquired HIV undergo an acute seroconversion illness and that most of them remain undiagnosed.3 Those with a severe and long lasting illness have a poorer long term prognosis.4

The symptoms associated with primary HIV-1 infection are shown in the box. The most specific include a maculopapular rash affecting predominantly the upper part of the body and mucosal ulcers affecting the mouth and genital areas. Patients may also present with a predominantly gastrointestinal syndrome, which includes abdominal pain, nausea, vomiting, diarrhoea, hepatitis, and even gastrointestinal haemorrhage. Rarer presentations of encephalopathy, pneumonitis, and rhabdomyolysis associated with acute renal failure may also be encountered. As severe acute immunosuppression may occur during primary HIV-1 infection, AIDS defining illnesses may also develop and should arouse suspicion of seroconversion in patients with a recent negative result on HIV testing.

Differential diagnosis

Clinically the differential diagnosis of this acute retroviral syndrome includes mononucleosis caused by Epstein-Barr virus or cytomegalovirus, toxoplasmosis, rubella, syphilis, viral hepatitis, disseminated gonococcal infection, herpes simplex virus, typhus, acute Crohn's disease, and other viral and spirochaetal illnesses. Syphilis remains the main differential diagnosis in cases with a rash and mucocutaneous ulceration, a rare occurrence in Epstein-Barr virus (except the ampicillin rash), cytomegalovirus, and toxoplasmosis.

The laboratory investigations required to confirm a clinical suspicion of primary HIV-1 infection are measurement of p24 antigen, which becomes detectable early after infection with HIV in many but not all cases, together with western blotting and the enzyme linked immunosorbent assay (ELISA) antibody test. If suspicion is high and these tests give negative results they should be repeated a few days later together with direct viral identification using the polymerase chain reaction. Other less specific laboratory signs include a CD4 lymphopenia, a CD8 lymphocytosis, mild anaemia, thrombocytopenia, abnormalities on liver function tests, and atypical lymphocytes.2

Figure 1 shows the immunological consequences of the host-viral relation.5 During primary HIV-1 infection the peak of viral replication is associated with the widespread seeding of a relatively homogeneous viral population throughout the body. This coincides with the acute illness and activation of the immune system, which eventually reduces viral load.

Fig 1

Changes in CD4 cell counts (*) and plasma viraemia (*) during HIV infection (modified from Fauci5 with permission). During primary infection CD4 cell counts drop while plasma viraemia—measured by p24 antigen assay or polymerase chain reaction—is high, and in this early period HIV antibody levels can still be undetectable

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Recently, emphasis has been placed on early antiviral intervention, even as early as the “seroconversion illness,” when it may be possible to limit the initial dramatic peak of viral dissemination and fall in CD4 cell counts. Without treatment the CD4 cell count bounces back to suboptimal levels after an initial drop (fig1), followed by an individually variable but relentless decline in CD4 numbers. Early antiretroviral treatment may alter this process, prevent the decline in CD4 cell count, and prolong a patient's disease free period and life expectancy. Preliminary data with zidovudine indicate that antiretroviral treatment is well tolerated, with a beneficial effect on both the CD4 cell count and the occurrence of minor opportunistic infections in the absence of new viral resistance.6 It will be important to assess a “hit hard and early” approach using antiretroviral combination therapy from the rapidly growing number of drugs available.7 Treatment should be started as soon as evidence of HIV infection is gathered and maintained for at least six months.6

Three challenges

Thus the challenges of primary HIV-1 infection are threefold. Firstly, it presents an opportunity to diagnose HIV infection early, before a patient presents with opportunistic infections and advanced collapse of the immune system. Secondly, it provides a chance to decrease transmission through early counselling and education. Thirdly, the recognition of primary HIV-1 infection as a clinical entity may allow us the opportunity to hit hard and early with the latest and most effective treatments. To meet these challenges will require effort from HIV referral centres to generate information about the clinical manifestations of primary HIV-1 infection. This in turn will facilitate its early recognition and permit referral of suspected cases for urgent p24 antigen and HIV serological testing as medical emergencies for early treatment.