New research presented at the 13th Conference on Retroviruses and Opportunistic Infections (CROI 2006) lends further support to procedures that can identify cases of primary or acute HIV infection. Not only can the detection of primary HIV help public health efforts to stem HIV transmission; in rare cases, researchers suggest, it may alert clinicians to the presence of advanced HIV disease in a person who never seroconverted, allowing that person to receive antiretroviral therapy before it is too late.

Primary HIV infection is the period immediately after a patient is initially infected with HIV until he or she develops antibodies to HIV that are detectable by ELISA and Western Blot assays. Generally, people experiencing primary HIV infection have an extremely high viral load and clinical symptoms such as fever, rash and sore throat.

Throughout much of the epidemic, diagnosing primary HIV infection has been a challenge. Traditional antibody assays cannot detect the virus until a minimum of four to six weeks into infection, and the symptoms with which a patient may present -- if the patient decides to see a doctor at all -- can be ascribed to many other illnesses.

However, the period of primary HIV infection remains an important public health concern. Many studies have shown that besides the period of end stage disease, it is during this early period when a person is probably the most infectious. Almost by definition, a person experiencing primary HIV infection has engaged in some recent "high-risk" activity that led him or her to acquire HIV, and that activity may be continuing, which would allow the further spread of HIV. It is estimated that 40% of HIV-infected patients acquired HIV from someone who was in the primary infection stage. Thus, diagnosing primary HIV infection is critical, so that appropriate risk-reduction counseling can be given. A number of studies presented at CROI 2006 examined the use of methods that can improve our ability to detect primary infection.

Spotting High-Risk Cases More Often, and Earlier

In one study, investigators from San Francisco reported on their experience with diagnosing primary HIV. Hong-Ha Truong, from the University of California-San Francisco, and colleagues evaluated 3,800 people who voluntarily presented for confidential HIV testing at San Francisco's municipal sexually transmitted disease clinic. They found that 125 people were diagnosed with HIV by standard testing with enzyme-linked immunoassays, which detect antibodies directed against HIV. In addition, the researchers used nucleic acid amplification testing to further examine samples from all those who initially tested "HIV uninfected." Nucleic acid amplification testing looks for the presence of HIV directly and thus can identify people who were experiencing primary HIV infection. Using this method, the researchers found an additional 11 individuals who had detectable HIV but had not yet developed an antibody response to HIV, increasing the rate of HIV detection by nearly 9%.

Compared to those individuals who were truly HIV uninfected, patients in primary HIV infection were more likely to have a known HIV-infected partner (P = .05), a history of hepatitis B (P = .002), a history of syphilis (P < .0001) and a history of chlamydia (P = .003). It is important to remember that these patients were likely to be very infectious; many subsequent cases of HIV infection may have been prevented by identifying these cases and providing appropriate risk-reduction counseling.

Primary HIV Testing and Late Seroconverters

On the other side of the country from San Francisco, public health officials and investigators from North Carolina have for the last several years reported on a statewide program to identify people in primary HIV infection. The program tests for the presence of HIV in samples that are ELISA negative through an automated strategy that performs viral load testing on samples pooled from many individuals. If a pooled specimen is found to be positive by viral load testing, subsequent nucleic acid amplification testing identifies the individuals who are experiencing primary HIV infection. The public health officials then perform extensive contact tracing to identify other HIV-infected or exposed individuals.

Susan Morpeth, from the Duke University Medical Center, and colleagues reported on a cohort of people derived from this public health effort from 1998 to 2005. Their aim was to examine a relatively cloudy area of HIV pathogenesis: The time it takes an individual to seroconvert, and the bearing this may have on that individual's level of disease progression. They included 72 individuals who had been diagnosed with HIV within 30 days of seroconversion, whether their ELISA was initially negative or positive. Overall, 89% were male and 54% were white.

The researchers found that, compared to people who were already ELISA positive, those who were still ELISA negative had a higher HIV RNA (5.7 million versus 310,000 copies/mL, P < .0001) and had become symptomatic more recently (9 days versus 25 days, P < .0001). This is to be expected, given the natural history of primary HIV. The investigators also found that ELISA-negative individuals were more likely to be non-white (P = .03). The reason for this is unclear, although the authors suggested that a diagnosis of HIV may have been considered earlier in non-white individuals.

Morpeth et al also described a single unusual case in which an individual did not develop an antibody response for one year after first having a viral load of more than 10 million copies/mL. This patient had rapidly progressive HIV, with a CD4+ cell count of 2. He did not develop a positive antibody response until five months after starting an effective combination of antiretroviral medications. Similar cases have rarely been reported in the literature, but they do happen. It is worth noting, of course, that the diagnosis would not have been made -- and treatment would not have been initiated -- without appropriately testing for primary HIV infection.

That said, beyond this rare case of delayed seroconversion, the value of initiating treatment during primary infection has been a matter of debate among physicians. Uncontrolled, preliminary studies suggested that administering antiretroviral therapy during primary HIV would prevent destruction of the immune cells that are programmed to fight HIV, allowing patients to subsequently control HIV without antiretrovirals. Unfortunately, larger, controlled trials did not find this to be true.

However, although instituting combination antiretroviral therapy during primary HIV infection is controversial, the public health importance of diagnosing HIV-infected people as early as possible is undeniable. Both the North Carolina program and the study results from San Francisco show that widespread testing for primary HIV is feasible and can facilitate getting newly HIV-infected people into care, where they can receive medical attention and risk-reduction counseling. In addition, the closer-than-usual proximity to the date of infection makes partner tracing more feasible, and can further strengthen the public health effort against the HIV epidemic.