Seroreversion in patients receiving HAART during acute infection 2

Within 8 weeks, typically, of HIV entering the body, the human immune system has launched its ill-fated counterattack and churned out enough HIV-targeting antibodies that sensitive diagnostic tests can detect them. These antibodies remain detectable in the vast majority of people throughout their battle with HIV. But researchers in Boston recently reported that three out of 150 HIV-positive patients who began highly active antiretroviral therapy (HAART) soon after becoming infected never developed the full array of detectable antibodies, or they stopped producing some or all of the diagnostic antibodies they had once made (Clin Infect Dis 2005; 40:868-873).

The clinical significance of either failing to fully 'seroconvert' and make detectable HIV antibodies or to 'serorevert' and stop making them is completely unknown, says co-author Eric Rosenberg of Massachusetts General Hospital, who points out that the antibodies detected by HIV diagnostic tests do not themselves neutralize the virus. We have no reason to suspect that seroreversion or failing to seroconvert is a good thing, nor do we have reason to suspect that it's a bad thing. It's just puzzling.

Rosenberg and his colleagues were studying cellular immune responses of patients who initiated HAART during acute HIV infection, when they spied the trio of unusual cases. The three men, who began the therapy 1-16 days after seeking medical care, achieved and maintained undetectable HIV levels after 2-6 months of treatment. However, one of them never developed a fully evolved HIV-1 antibody response during 56 months of follow up. The other two patients developed HIV antibody responses but lost them about 7 and 26 months after starting therapy.

The findings will likely add to the ongoing debate about when HAART should be started. Both seroreversion and the failure to seroconvert are extremely rare occurrences, which have been attributed to a variety of causes including deteriorated immune systems, particularly rapid disease progression and the loss of passively transferred maternal HIV-1 antibodies in non-infected infants. This is the first published report of either phenomenon occuring in patients treated with conventional HAART during acute infection.

We wouldn't expect HAART initiated later on to result in this kind of effect, says lead author Sigall Kassutto. It seems to be HAART plus the timing of HAART. Current guidelines recommend initiating antiretroviral therapy for individuals with longstanding infection whose CD4 cell counts have dropped below 200 × 10⁶ cells/l, and considering it when CD4 cell counts fall between 200 × 10⁶ and 350 × 10⁶ cells/l. However, there is interest in starting HAART during early stages of infection to enhance or preserve the body's own HIV-specific immune responses.

The only explanation we have for why these antibody responses waned is that HAART was so effective early in infection that it somehow tempered or altered the otherwise normal generation of antibodies, Rosenberg says. It may not have any meaning clinically, but it gives us some insight into a complex interplay between virus, immune response and therapy.

Kassutto and Rosenberg plan to explore the ability of the three men, who remain on therapy, to produce HIV-neutralizing antibodies. And if they ever have a viral rebound, or if they ever elected to come off antiretroviral therapy, Rosenberg adds we would certainly aggressively study what happens to their HIV antibodies.