Diagnosis of acute HIV infection: it’s time to get moving!
Editorial by Timothy Flanigan, MD; and Karen T. Tashima, MD for Annals of Internal Medicine
Despite dramatic advances in the treatment of HIV infection and the resultant decrease in deaths from AIDS, new HIV infections continue to occur among Americans at a relatively steady rate of 40 000 to 45 000 per year. More than 90% of cases of acute HIV infection go undiagnosed despite the fact that more than 50% of persons with the disease are symptomatic. Although many of these symptomatic patients seek medical attention at emergency departments, urgent care centres, and primary care offices, they often receive the true but highly misleading diagnosis of “viral syndrome” and are told to go home, take aspirin and plenty of fluids, and call if the symptoms do not resolve. Usually, the symptoms do resolve. Acute infection occasionally has severe sequelae, which may include neurologic syndromes (such as meningitis or myelopathies) or opportunistic infections caused by profound decreases in CD4 cell count (such as Pneumocystis carinii pneumonia or Candida esophagitis).
Why have we, as a medical profession, been so lax in diagnosing acute HIV infection? There are two primary reasons. The first is that treatment and often diagnosis of HIV infection have been relegated to specialists. Sometimes this is due to lack of knowledge of newer tests or therapies, and sometimes it is due to discomfort related to the difficult issues surrounding HIV, such as high-risk sexual behaviour and substance abuse. Sometimes it is simply caused by a clinician’s inability to spend the additional time that the subject of HIV frequently requires. Relegating diagnosis and management of HIV infection to specialists has severely impaired our ability as a profession to diagnose this syndrome. Patients with primary HIV infection most often present to non-HIV specialists, such as dermatologists, emergency department physicians, or primary care physicians, with mononucleosis-like symptoms, including fever and myalgias. Rather than considering acute HIV infection and ordering the appropriate tests, the clinician often refers the patient to a specialist in some other building and some other part of town. More often than not, the patient never gets there.
The second reason it has been difficult to diagnose acute HIV infection is that laboratory testing can be complicated and the results may be difficult to interpret. The article by Daar and colleagues in this issue [of Annals of Internal Medicine] provides an important contribution regarding appropriate testing for acute or “primary” HIV infection. The authors pooled their collective experience among three cohorts involving 436 patients to evaluate the sensitivity and specificity of two different testing strategies. Patients who were potentially exposed to HIV through high-risk sexual behaviour or needle sharing and had symptoms compatible with primary HIV infection were referred for evaluation at two centres in California. Primary HIV infection was diagnosed in 54 patients (12.4%).
The authors evaluated a commercially available p24 antigen assay and a commercially available plasma HIV RNA assay that used branched-chain DNA. The latter test is frequently referred to as a plasma viral load assay and is used to monitor chronic HIV infection, particularly the effectiveness of therapy. The costs of these two assays are quite different (at our institution, a patient is charged $220.00 for a plasma viral load assay and $75.00 for a p24 antigen assay, although the actual cost is significantly less). In the study by Daar and colleagues, the p24 antigen assay had a sensitivity of 88.7% for primary infection in patients who had negative results on enzyme immunoassay or an indeterminate result on Western blot, compared with a sensitivity of 100% for the plasma viral load assay. The specificity of the p24 antigen test was 100% compared with 97.4% for the plasma viral load assay. Patients with primary HIV infection who had a negative result on enzyme immunoassay or an indeterminate result on Western blot had a plasma viral load that consistently exceeded 100 000 copies/mL.
The HIV-1 plasma viral load assay is certainly newer and, because it is based on polymerase chain reaction technology, “higher tech.” However, these results demonstrate that the plasma viral load assay is costly and may be less useful for screening large numbers of persons in whom the prevalence of primary HIV infection is relatively low. Although the plasma viral load assay has better sensitivity, its relatively poor specificity may make it less desirable for screening in primary care settings. For individual circumstances, physicians may choose to use the plasma viral load assay because of its better sensitivity. In a symptomatic patient with negative results on enzyme immunoassay or an indeterminate result on Western blot, a plasma viral load less than 10 000 copies/mL should be interpreted cautiously as a potentially false-positive result.
The costs and benefits of screening for acute infection with these two assays can be demonstrated as follows. In a large urban emergency department that has 50 000 visits per year, one might anticipate screening 500 patients for primary HIV infection on the basis of symptoms. If 1% of persons screened, or 5 of 500, had primary HIV infection, then the p24 antigen assay would be expected to diagnose HIV infection in at least 4 of these patients without any false-positive results. On the other hand, if a plasma viral load assay was used, 5 of 5 primary infections would be detected, but up to 3% of persons screened, or 15 persons, might have a false-positive result. In these circumstances, the false-positive plasma viral load is usually low (<10 000 copies/mL), whereas in true-positive cases of primary HIV infection, the plasma viral load is usually more than 100 000 copies/mL. Extensive counselling, as well as further testing, would be necessary for the 15 patients with false-positive results, and the emotional toll would also be great. For large-scale screening, the p24 antigen assay seems to be more desirable, although it will miss a small number of HIV-infected persons. The cost of screening 500 people by p24 assay at $75 per test, in addition to the standard HIV serologic assays, is $37 500. In comparison, it would cost $110 000 to screen 500 people by viral load assay at $220 per test.
Do symptoms help predict which persons might have primary HIV infection? In the study by Daar and colleagues, patients with primary HIV infection were significantly more likely to report fever, myalgia, arthralgia, rash, and night sweats. Combining fever, myalgia, and rash increased the predictive value of symptoms; however, no combination of symptoms identified more than 75% of patients with primary infection. Because these symptoms are highly nonspecific, no good symptom scale can definitively indicate which patients should be tested for primary HIV infection.
It is also important to realize that screening for primary HIV infection should not be limited to persons with “high-risk” behaviours, because this categorization leads clinicians to miss most patients with heterosexual or unspecified risk factors. Although the study by Daar and colleagues was carried out in Los Angeles and San Diego, where men with primary HIV infection were more likely to be homosexual, this cannot be assumed to be the case in other regions of the country. The HIV epidemic is spreading most rapidly among heterosexual persons, particularly adolescents and young adults nationwide. Limiting screening for primary HIV infection to certain risk groups would be a mistake.
Diagnosing primary HIV infection can be enormously beneficial, both from the individual and public health perspectives. Persons who receive appropriate counselling may decrease their high-risk behaviour and thereby decrease HIV transmission. Identification of new infections will allow the development of targeted prevention strategies throughout relevant communities. Patients who receive a diagnosis of primary HIV infection should be considered for early therapy and should be screened for other infections, such as sexually transmitted diseases, hepatitis, and tuberculosis. In addition, they should be vaccinated to prevent pneumococcal pneumonia and hepatitis A and B. The National Institutes of Health have funded a national (US) network (the Acute HIV Infection and Early Disease Research Program [AIEDRP]) that will coordinate research efforts to better understand immunologic and virologic events associated with primary HIV infection. Because early treatment of HIV infection may provide better immunologic control of infection, providers and patients are encouraged to consider enrolment in trials of primary HIV infection.
The broader medical community has successfully incorporated routine HIV testing among pregnant women regardless of risk group. We now need to take the next step and incorporate screening for primary HIV infection among all patients who present for evaluation with compatible symptoms. Primary care physicians and the primary care network, which includes health care clinics, urgent care centres, and emergency departments, should consider evaluating primary HIV infection by using the standard serologic tests enzyme immunoassay and Western blot and adding a p24 antigen assay for all persons with compatible symptoms. Primary care physicians should immediately begin to integrate routine screening for acute HIV infection so that individual patients and communities may benefit as soon as possible.
The fully referenced text of this editorial is available at:
The full text of the “Brief Communication” from Daar and colleagues is also available at: