by Bob Roehr
MONTREAL, Canada –
People with a CD4 count above 500 who waited to start therapy had a 36 percent higher risk of death than those who started highly active antiretroviral therapy (HAART).
The data presented in Montreal at the 16th Conference on Retroviruses and Opportunistic Infections provided further evidence for the movement toward earlier initiation of therapy.
The analysis was the second installment of an unusual collaboration between all 22 HIV research cohorts in North America that followed patients between 1996 and 2006. The first part, released last October, involved patients starting or deferring patients with a CD4 count between 350 and 500. It found a 70 percent greater risk of death from waiting. The new study in those with higher CD4 counts involved 9,174 patients and 25,337 person-years of follow up. Some 2,620 (29 percent) initiated HAART above 500 while the majority (6553, 71 percent) deferred to some later point.
"Our finding suggests that therapy earlier in HIV infection could significantly prolong survival," said lead author Mari Kitahata, a researcher at the University of Washington. Neither baseline CD4 count nor viral load were predictors of mortality. Increasing age was the only significant predictor of death.
In Europe, the When to Start Consortium examined 15 cohort studies and reached similar conclusions at lower CD4 ranges but not at the higher ones. Lead author Jonathan Sterne, from the University of Bristol, said, "Delaying to below 250 was clearly associated with increased rates of AIDS and death. We found that starting above 350 was beneficial to deferring…but we didn't find benefit from starting above approximately 400."
He added, "Starting above 350, the absolute rates of mortality and absolute rates of death and dying are actually relatively low. So, the higher you put your threshold, the smaller the absolute benefit becomes." The costs may outweigh the benefits.
Kitahata pointed to emerging data that the ongoing inflammation of untreated HIV infection contributes to risk of heart disease, diabetes and likely premature aging. "These help to understand why HIV is persistently creating defects in the immune system." She said the collaboration is beginning to analyze these and other clinical events in the cohort datasets.
"We would like the message to be the earlier you come into care, the better we can care for you," she said, adding that vaccinations are more effective and comorbidities often are easier to treat and resolve.
"All of the data seems to be pushing in the same direction – studies on immune activation, cardiovascular disease, malignancies – it's all snowballing in favor of earlier therapy," said Johns Hopkins University infectious disease guru John Bartlett.
He also believes that an earlier start to treatment will have a public health benefit by reducing viral load and the number of new infections.
Conference chairman John Mellors from the University of Pittsburgh said concern over the toxicities of therapies had moved the field "toward the precipice" of serious HIV disease before initiating therapy. "Now I sense that we are moving away from that to higher and higher CD4 starting points."
Very early treatment
Researchers have been tantalized by the possibility that treating HIV infection during the first few weeks after exposure might allow the immune system to better control of the virus and significantly change the course of disease.
New evidence from an ongoing cohort study at the Academic Medical Center in Amsterdam teased at that possibility but did not have a conclusive answer to the question.
It looked at 102 patients who had detectable virus in their blood but were negative or indeterminate on tests for antibodies to HIV. Antibodies generally develop 1-3 months after initial infection, so these patients were within that three-month window.
Patients were randomized to receive no treatment (47) or temporary HAART for six or 15 months (55) before stopping. They continue to be followed and this analysis was for the five-year period March 2003 to February 2008.
About half of the first group (23/47) who did not initially start treatment would later do so because of falling CD4 count and rising viral load. Some 10 patients who received early HAART and then an interruption would later restart therapy for the same reasons. Those in the untreated group went an average of 126 weeks before starting HAART, while those in the treated group restarted therapy after an average of 181 weeks off of treatment.
"Early treatment prolonged time off treatment by more than a year," said researcher Radjin Steingrover. Just how close to the point of infection these patients started therapy is unclear.
"We only have data from the time of seroconversion to the start of treatment, on average that was three weeks," said Steingrover.
The most intriguing fact is that "five patients (about 10 percent) have an extreme amount of viral control after treatment and interruption, they may very well be long-term non-progressors," said Steingrover. "Several of them have (viral loads) less than the limit of detection over a couple of years."
Study of individual patients suggests that starting therapy closer to the point of infection has the greatest impact on bolstering the immune response and affecting the long-term course of HIV infection.
The window for intervention likely is only a few weeks long, perhaps only a few days. This makes it difficult to study the phenomena, and nearly impossible to envision very early intervention as a major treatment strategy. However, insights from studying very early intervention may provide insights to developing a vaccine that helps patients better control the virus.
