"If you want a bottom line, it's that we should all be actively looking for patients in the acute stages of HIV infection and either treating them or getting them into studies."
-- Eric Rosenberg, M.D.
Harvard Medical School
The PRN Notebook, June 2001
There are no definitive answers to these questions, but scientific evidence thus far suggests there are some good reasons for exploring PHI. Theoretical rationales cited for identifying, treating, and studying patients with PHI have generally been described as follows:
While there was hope early during the development of highly active antiretroviral therapy (HAART) that treatment during PHI would decrease viral seeding of lymphoid tissue and facilitate eradication, this strategy is no longer feasible. It is now known that viral reservoirs are established in resting memory CD4 T cells early in infection and certainly before the development of HIV-specific antibodies.
The initial host-virus interaction during PHI represents a unique window of opportunity for intervention and for studying HIV immunopathogenesis. Many researchers speculate that such study will ultimately lead to a better understanding of the parameters of effective immune control of HIV and eventually result in the development of an effective vaccine or other method of immune-mediated viral containment.
The course and time frame of the infection is illustrated graphically in Figure 1. As noted earlier, the course of PHI is limited to a few weeks or months, whereas the entire course of HIV infection can span many years.
Specifically, PHI is the period after infection with HIV but before the development of detectable antibodies. It is a period of active HIV replication and transient immune suppression. Viremia rises rapidly in the plasma, often reaching levels in excess of 1 million copies per milliliter, with widespread dissemination into lymphoid organs throughout the body. While some patients have no clinical symptoms during PHI, it has been estimated that 50% to 90% of patients are symptomatic with an illness resembling infectious mononucleosis or influenza and that a large percentage of these patients present for care at health care facilities.2 This symptomatic manifestation of infection is generally referred to as "acute retroviral syndrome" (ARS). Some of the most prevalent symptoms associated with ARS are listed in Table 1.
The exact determinants of the viral set point are not known, but factors such as the immune response of the host, the number of available target CD4 T cells, the host's degree of immune activation, the extent of trapping and sequestration of HIV and infected CD4 T cells in the germinal centers of lymphoid tissue, as well as the replicative capacity of the viral strain, may contribute to the set point.6,7 The set point generally predicts the rate of disease progression, suggesting that this initial viral-host interaction during PHI is critical in HIV immunopathogenesis.
Who Is Suspect for PHI?The problem with identifying PHI patients is two-fold. First, the symptoms associated with ARS are nonspecific and can mimic other common illnesses. Second, there is no single diagnostic test that is cost-effective and sufficiently specific and sensitive enough to conduct broad-based testing of the suspected patient population.
Studies have been conducted to determine the usefulness of symptoms and virologic tests for diagnosing PHI. Daar et al. recently published a prospective cohort study of 436 patients with potential exposure to HIV who reported symptoms compatible with PHI.8 In this study patients were referred from clinics, testing centers, emergency departments, and community physicians to 2 research hospitals in Los Angeles and San Diego. The patients were divided up by institution and time into 3 cohorts as outlined in Table 2. The demographics of the 3 cohorts were similar. Overall, 89% of the study patients were male; also 74% were white, 13% Hispanic, and 9% African American. Seventy-seven percent of the patients were gay men, 18% heterosexual women, and 4% intravenous drug users.
PHI patients were more likely to be gay and exposed to an HIV-infected person. A comparison of symptoms showed that PHI patients were more likely to experience fever, myalgia, arthralgia, rash, or night sweats. Only these symptoms and the lack of nasal congestion turned out to be statistically significant predictors of PHI. (See Table 3.) Combining fever, myalgia, and rash increased the predictive value of these symptoms. However, no combination of symptoms identified more than 75% of PHI patients.
In contrast, Frederick M. Hecht, M.D., co-director of the Options Project at the University of California, San Francisco has reported some slightly different results.9 The Options Project, which has been in existence since 1996, has screened 444 patients for PHI and early HIV infection. (Early infection is defined as infection and subsequent seroconversion within 12 months of entering the study.) Hecht has been quoted as stating that "[T]he key symptoms [are] rash and fevers, followed by loss of appetite, arthralgias, and pharyngitis." Using logistic-regression models, this group has determined that the odds of rash predicting PHI are 3.7 (p=0.002) and the odds of fever predicting PHI are 3.4 (p=0.009). According to Hecht, "In other viral infections, we don't often see fevers and we rarely see rash. These two symptoms, especially if accompanied by some of the other symptoms frequently seen in PHI, should heighten the level of suspicion."9
Diagnosis of PHIDuring PHI there is a "window period" of approximately 2 to 3 months after initial infection before HIV-specific antibodies in the blood can be detected by the standard antibody test (ELISA). During this window period other tests must be used to diagnose PHI. The most common tests used to diagnose PHI are the quantitative HIV RNA (viral load), which uses polymerase chain reaction to detect the presence of HIV, and the p24 antigen test, which detects a viral protein and indicates ongoing viral replication.
In an ideal world a screening test for PHI would have 100% sensitivity. A test with that level of sensitivity would detect everyone who has been infected with the virus (i.e., no one who was positive would go undetected). The perfect confirmation test would also be one that has 100% specificity (i.e., there would be no false-positive results). It is important to note that, in the context of PHI, testing for HIV antibodies is irrelevant since by definition PHI patients have not been infected long enough to develop HIV-specific antibodies.
Unfortunately, current tests used in PHI are neither 100% sensitive nor specific. In the study cited above, Daar et al.8 tested patients in the 3 cohorts for p24 antigen and HIV RNA. Because there is no current gold standard test for HIV infection, the authors assumed that the HIV RNA test was 100% sensitive. The results showed that while the p24 antigen test has a specificity of 100% (there were no false positives), it only has a sensitivity of 88.7% (5 of the 40 PHI patients were not detected by the test). Also, while the researchers assumed that the HIV RNA test had a sensitivity of 100%, the study results demonstrated that the test had a specificity of 97.4% (8 of the 303 patients tested had false-positive results as confirmed by repeat testing). A more detailed summary of the results is listed in Table 4. Because the specificity of the HIV RNA test is not 100%, most experts recommend that results with low viral titer (less than 10,000 copies/mL) be approached with caution since they may be false positives.
The problems with these tests are further complicated by their relative costs. While the p24 antigen test is cheap and easy to access, studies have demonstrated that it may fail to detect up to 20% to 25% of PHI patients. In fact, Christopher D. Pilcher, M.D., of the University of North Carolina has determined that p24 positivity is time dependent; it may be necessary to test within 3 weeks of the onset of PHI symptoms to get an accurate reading.10 After 3 weeks, up to a quarter of PHI patients will have negative p24 antigen test results. (See Figure 3.) On the other hand, while the HIV RNA test is highly sensitive, it is a relatively expensive test that may still result in some false-positive readings.
Obviously, the choice of tests will depend on the circumstances. For general screening, the HIV RNA may not be cost effective and a p24 antigen test may be more appropriate. However, when patients exhibit symptoms and behavior that are highly consistent with HIV infection, an HIV RNA test may be merited.
In addition to the virologic tests described above, the differential diagnosis for presumptive PHI includes viral hepatitis, mononucleosis, herpes virus infection, anthrax infection, and secondary syphilis. A complete blood cell count usually reveals lymphopenia, thrombocytopenia, and atypical lymphocytes.
Patients suspected of having PHI should be screened for other sexually transmitted diseases, including syphilis and hepatitis. Conversely, patients with other STDs should be prospectively identified as high-risk for PHI.
ConclusionsRecognizing PHI in a patient remains a tricky business. There is some evidence to indicate that PHI symptoms may be nonspecific. However, some researchers point to the presence of rash and fever as being particularly predictive of PHI. Taking a history of a patient's risk behaviors including unprotected sexual encounters and sharing of needles is critically important. Physicians should be aware that patients are often reluctant to disclose that type of information. A physician therefore must maintain a higher level of suspicion for HIV infection. Clinicians should remember that p24 antigen tests, while inexpensive and easily accessed, may miss a large percent of PHI patients. There is evidence that the accuracy of p24 antigen tests results may be time dependent. Patients tested after 3 weeks of the onset of PHI symptoms are likely to be missed by p24 antigen tests. In cases where risk behavior and symptoms indicate a strong possibility of PHI, an HIV RNA test may be merited. However, treating physicians should remember that some false positives will result and HIV RNA results with low copy numbers are especially suspect for being false positives.
Although treatment guidelines promulgated by the US Department of Health and Human Services recommend that clinicians offer antiretroviral therapy to patients with PHI,12 treating this early stage of infection remains controversial. The toxicities of anti-HIV drugs are now widely known and the guidelines provide no direction on the duration of treatment for PHI. Consequently, some clinicians are reluctant to offer a hazardous, open-ended course of therapy to patients who will suffer no ill effects from HIV infection for years.
Still, properly recognizing and diagnosing PHI has merits, not the least of which is accurately informing patients of the nature of their illness and treating it in a way appropriate to the circumstances. Other compelling theoretical rationales, discussed in greater detail in other articles in this issue, argue for at least enrolling patients with PHI in clinical trials where available, and perhaps for treating them. Time will tell if the effort, time, and money spent on identifying, diagnosing, and studying PHI patients will have been worthwhile. However, ignoring this phase of HIV infection will only insure that critical questions about transmission and pathogenesis might never be fully answered.
Back to the RITA! Winter 2002 contents page.
The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.