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September 20, 2006
Treating Primary HIV Infection: Is There a Benefit?
by Tim Horn
September 20, 2006 (AIDSmeds)—Should treatment be initiated in people diagnosed with HIV in the earliest days of infection? Researchers involved in the study of primary HIV infection (PHI) – the initial stage of HIV infection in the body – have been attempting to answer this question for several years. While there has been some data indicating that treating PHI is associated with short-term benefits, there has been very little research indicating that it translates into long-term benefits. But new research, published in the September 15th issue of the Journal of Infectious Diseases (JID), suggests that long-term benefits may in fact be possible for some patients.
PHI is generally characterized as the period immediately following HIV infection in which the viral load is extremely high, the CD4 (T4) cell count is low, and antibodies to the virus are in the process of being produced. PHI can last six to 12 months following infection and ends when the viral load and CD4 cell count have achieved "steady state" levels – a balance of virus production and T-cell destruction that is maintained, often for several years, until the immune system begins to falter and HIV gains the upper hand.
Researchers have come up with a number of theories as to why HIV treatment should be started during PHI. First, it may prevent HIV from irreversibly damaging sanctuaries of CD4 cells in the body, including the gut. Second, it may slow HIV's replication and the production of mutated versions of the virus that can be difficult for the immune system to identify and fight. Finally, it may help protect specific CD4 cells in the body that stand the best chance of coordinating the immune system to fight HIV, before they are permanently destroyed by the virus.
A review paper published in AIDS in 2004, titled "Is Antiretroviral Treatment of Primary HIV Infection Clinically Justified on the Basis of Current Evidence," indicated that there are short-term benefits associated with treatment during PHI. The paper looked at several studies in which newly infected patients were started on treatment, continued therapy for several months, and then stopped their drug regimens. Indeed, 12 to 24 weeks after treatment was discontinued, viral loads were lower and CD4 cell counts were higher in PHI-treated patients compared to untreated PHI patients. "However," the authors wrote at the time, "there is currently no evidence from these studies to suggest that therapy during PHI results in a reduction in clinical progression compared with use of effective therapy in later disease, nor are there comparative data to suggest that short-term use of [HIV treatment] during PHI can alter future disease progression."
Two years later, there are new data to suggest that treatment during PHI may, in fact, alter HIV disease progression in certain individuals. The paper, published by Frederick M. Hecht of the University of California, San Francisco, and his colleagues with the Acute Infection and Early Disease Research Program (AIEDRP), involved 58 people from around the United States who began treatment during PHI. They were compared to 337 people participating in the AIEDRP but decided against early treatment.
Among the 58 patients who initiated treatment during PHI, 13 "acute" patients began therapy approximately five weeks after becoming infected with HIV. The remaining 45 "early" patients began therapy approximately ten weeks after becoming infected with the virus.
The 58 treated patients remained on therapy – usually a protease inhibitor-based regimen – for approximately 70 to 80 weeks. Their viral loads and CD4 cell counts were then evaluated 24, 48, and 72 weeks after stopping treatment and compared to the 337 patients who entered the study with PHI but elected not to start treatment.
24 weeks after stopping treatment, the acute- and early-treated patients had viral loads that were approximately 0.5 log lower than the untreated patients 24 weeks after they enrolled in the study. What's more, CD4 counts were approximately 115 cells higher in the treated patients compared to the untreated patients.
72 weeks after stopping treatment, there was no statistically significant difference between the 58 treated patients and the 337 untreated patients in terms of viral load and CD4 cell count differences. However, when the researchers only looked at the 13 acute patients, significant differences were seen. The acute patients had viral loads approximately 0.68 log lower than the untreated patients after nearly three years of off-treatment follow up. CD4 counts were also 125 cells higher in the acute treated vs. untreated patients after 72 weeks. The 72-week viral load difference, the researchers suggested, was associated with a 50% reduction in the risk of progression to AIDS over six years, based on a widely accepted disease progression model from the Multicenter AIDS Cohort Study (MACS).
These data, Dr. Hecht's group concluded, "suggest that treatment given during acute HIV infection may modify the long-term course of disease." As for the potential long-term benefits of treating early HIV infection – infection that has been established for several weeks – the data are less clear. Even the results involving the patients with acute HIV infection need to be interpreted cautiously, Dr. Hecht's group argues, on account of the fact that the actual number of patients who initiated therapy during acute HIV infection constituted a very small sample size and that longer follow-up is needed to assess the durability of benefit.