IAS: Early HIV Treatment Regaining Favor

SYDNEY, July 23 -- The pendulum of HIV treatment is starting to swing -- once again -- toward the "hit early, hit hard" theory.
This time, though, the shift in approach is not being driven by the hope of wiping out the virus but by the fear that delays in treatment expose patients to increased risk of a range of diseases not usually considered part of the HIV spectrum.
Researchers at the 2007 International AIDS Society meeting here are discussing plans for a study, to be called START, that would evaluate whether treatment should begin when patients have a near-normal CD4 cell count of 500, instead of 200 or lower.
"We can do the study now," said Fred Gordin, M.D., of the George Washington University HIV/AIDS Institute, and there's "compelling evidence" that the outcome might support the higher treatment level.
In a panel discussion, Dr. Gordin said that for years researchers have considered the time after initial HIV infection to be a latency period, during which there is no significant morbidity.
But recent studies suggest that even early on people with HIV are at increased risk of "non-AIDS" illnesses like myocardial infarction and cirrhosis, compared with people who don't have HIV.
The hypothesis is that the chronic inflammation associated with HIV infection is causing the increased risk and that keeping the immune system closer to a normal level of about 800 CD4 cells per microliter of plasma might have a benefit, he said.
"We need a new (treatment) paradigm" that tries to lower the risk, Dr. Gordin said.
Current guidelines suggest that treatment should begin when the CD4 count falls below 200 and should be "considered" when it dips under 350.
If the CD4 level is higher than that, treatment is generally deferred to avoid -- among other things -- the toxicity associated with HIV drugs, according to Mauro Schechter, M.D., Ph.D., of the Federal University of Rio de Janeiro in Brazil.
Dr. Schechter, speaking in a separate session, said many of the objections to early treatment are no longer valid.
For instance, newer HIV drugs are less toxic than earlier drugs, he said. They're also more potent, easing fears of resistance, and easier to take, which increases the chance that patients will follow their treatment plans faithfully.
The idea of early treatment is arising from such studies as the surprising SMART trial, which compared a regimen of steady HIV treatment to an interrupted plan, in which patients were treated only when their CD4 cell counts fell below 200.
As expected, those in the interruption arm had a significantly greater risk (at P<0.001) of the opportunistic infections characteristic of HIV: the odds ratio was 2.6 with a 95% confidence interval from 1.9 to 3.7.
But the study was stopped early when analysis showed that those in the interruption arm also had a significantly greater rate of non-AIDS diseases like heart attacks, according to James Neaton, Ph.D., of the University of Minnesota, who was part of the study team.
The odds ratio for cardiovascular, renal, and liver disease combined was 1.7, with a 95% confidence interval from 1.1 to 2.5, which was significant at P=0.009.
The implication, Dr. Neaton said, is that a consistently higher CD4 count protects against both AIDS and non-AIDS diseases, probably because it reduces the effects of chronic inflammation.
The data from the study provide "a strong scientific rationale" for going ahead with the START trial, Dr. Neaton said.
If it proceeds, the study would need to enroll about 3,000 people for a definitive result, Dr. Gordin said. Patients would be randomized to begin therapy at a CD4 count of 500 or to wait until the count was below 350.
Endpoints would be serious AIDS diseases, serious non-AIDS diseases, or death from any cause, Dr. Gordin said.
Like Dr. Schechter, Dr. Gordin said many of the objections to early therapy no longer exist, so that the START study is now feasible.
But, he added, there are also powerful reasons why it should be done now:
There is "compelling evidence of morbidity" in early HIV disease.
More and more people are aware of their HIV status.
There is an urgent need for definitive evidence on which to base clinical guidelines and decisions.
And the findings could have a "profound global public health impact."