HIV subtype efficient mortality predictor

Subtype D and AD lead to rapid deaths

A surprising finding from the research-rich Rakai (Uganda) cohort shows that a person’s HIV subtype is a significant predictor of whether a person might die quickly from AIDS than viral load, CD4 cell count, and other common predictors of disease progression.

"We found that 10% of the people with subtype D and recombinant virus incorporating D were dead within three years of being infected," says Oliver Laeyendecker, MS, MBA, senior research associate at The Johns Hopkins University School of Medicine in Baltimore, MD, and a senior research assistant at the National Institute of Allergy and Infectious Disease in Bethesda, MD.

The data tells investigators when people were infected, within a six-month window, so the timeline from HIV infection to death was well documented, Laeyendecker notes. "The shocking thing is those individuals did not have a significantly higher viral load than the general population of HIV patients."

Investigators also found that individuals with HIV subtype A had an average survival rate of nine years, whereas those with subtype D had an average survival rate of seven years, and those with a recombinant AD had an average survival rate of six years, Laeyendecker says.

All of the people who died within three years did not have a significantly higher viral load than those who took longer to die, Laeyendecker says.

"They all had mid-to-high range of viral load," he explains. "The people with really high viral loads were much more likely to die quicker than those who had very low viral loads, but when you stratified those individuals who died within three years and those who didn’t, there was no significant difference in viral load."

In the Rakai District of Uganda, where the study drew on a population-based cohort of 12,000 individuals, who have been interviewed and provided blood samples since 1994, 60% of the HIV infected population has subtype D. Another 20% have the recombinant AD, and 16% have subtype A, Laeyendecker notes.

Most studies about disease progression have been done in the United States and Europe where subtype B is prevalent, he says. "In Kenya, Uganda, and Tanzania, subtype D is endemic to these countries. In South Africa and India, the common subtype is C, and Thailand, the common subtype is recombinant AE and subtype B."

The Rakai cohort was part of a sexually transmitted disease (STD) intervention trial from 1994 to 1998. It studied the hypothesis that if people were tested for STDs then health officials could lower the incidence of HIV, Laeyendecker explains.

Since the study was longitudinal, investigators also could study the incidence of HIV infection and the probabilities of HIV transmission. Some of the many studies that have been published as a result of this cohort have found that pregnancy increases the risk of HIV acquisition, for example, Laeyendecker says.

The cohort maintains about 12,000 people in the study, and as some die or withdraw, they are replaced with others. "All of the people in the cohort with HIV infection were provided access to antiretroviral therapy in 2004," he says.

For the subtype study, researchers identified HIV subtypes and screened for recombinant virus, and then analyzed the data to see whether the people who had provided the original blood sample had died, Laeyendecker says.

Why researchers found this difference in subtype remains an unanswered question, he says.

Investigators have looked at co-receptor tropism in the Ugandan individuals and have found that 25% of the people with subtype D have dual tropic virus in which the virus infects both X4 and R5 receptors, Laeyendecker says.

"For subtype A, it’s a purely R5 virus, and for the recombinant strains it was about 16% dual tropic," he adds. Dual tropism played a role in rapid deaths, the data suggest. "About two-thirds of the people who had dual tropic virus from the time point that we did the assay were dead within three years," Laeyendecker says. "Tropism is determining which co-receptor the virus is using."

Investigators believe the reason why subtype D virus is more pathogenic is because a greater percentage of its virus uses co-receptor CCRX4, Laeyendecker says. "So subtype D is bad and D with X4 tropic virus is really bad," he says.

For researchers and clinicians working in Uganda and other places where subtype D is common, this knowledge suggests they monitor their patients with subtypes D or AD more closely than they do those with subtype A, but this may be difficult to achieve in the resource poor regions, Laeyendecker notes.