New Doctors treating people with HIV have faced a tough decision. Should patients begin drug therapy before AIDS symptoms appear, and put up with the inconvenience and potential side effects? Or is it better to wait until their CD4+ T cell count – a key barometer of the immune system’s health –drops below a certain level, even though that means a greater risk of transmitting the virus to a partner?
This summer an answer finally emerged. The international START (Strategic Timing of AntiRetroviral Treatment) study, the first large, randomized and controlled clinical trial of the issue, showed the benefits of early treatment so clearly that the trial was halted prematurely so the volunteers receiving deferred treatment could begin therapy.
“Early treatment was effective everywhere in the world,” says James Neaton, a University of Minnesota biostatistics professor and principal investigator for INSIGHT (International Network for Strategic Initiatives in Global HIV Trials), which designed and conducted the trial. “We had more than a thousand people enrolled from sub-Saharan Africa, and a total of 4,685 people from 35 countries.”
U.S. guidelines had already recommended treatment for all patients with HIV, but with the START results, physicians now have the backing of solid research when they ask symptom-free people to begin drug therapy.
“… [E]arly therapy conveys a double benefit, not only improving the health of individuals but … lowering their viral load, reducing the risk they will transmit HIV to others,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease (NIAID) – part of the National Institutes of Health and the study’s prime funder – in a news release. The results were first announced in late May, and the study appears online in the August 27, 2015 issue of the New England Journal of Medicine.
The University of Minnesota acted as regulatory sponsor for the trial, as well as its statistical and data management center.
START began in 2009 and enrolled HIV-infected volunteers ages 18 and older. At the outset, all had blood CD4+ levels above 500 cells per cubic milliliter and had not begun antiretroviral therapy. Study participants were randomly assigned to either begin drug therapy immediately, or defer treatment until their CD4+ level dropped to 350 cells per cubic milliliter or an AIDS-related or other event, such as pregnancy, prompted therapy to begin. The participants were followed for an average of three years.
When the study was halted, “we had a composite endpoint for AIDS and nonAIDS-related events – they dropped by 57 percent,” says Neaton. “The actual numbers were 42 versus 96 in the treated and deferred-treatment groups, respectively.” Early treatment had a larger impact on AIDS-related events. “They dropped by 72 percent, while nonAIDS events dropped 39 percent.”
A sub-study of one nonAIDS event – heart disease – presented a different result. At Hennepin County Medical Center, Jason Baker, M.D. ran the sub-study, which followed 332 participants across 10 countries and 17 sites, including HCMC, where more than 20 volunteers were enrolled. Baker, an associate professor of medicine and infectious disease specialist at the U of M, studied the effects of early therapy on blood vessel function, since vessel dysfunction precedes heart disease. This has become a big problem with HIV, he says, but it wasn’t known if drug therapy would help or hurt.
“One hypothesis is that with HIV infection, the immune system is more activated and causes inflammation in coronary arteries, yielding faster, earlier atherosclerotic disease,” Baker explains. “Starting HIV treatment might then reduce the risk for heart disease, given that it improves, though does not fully correct, these immune abnormalities. Another hypothesis is that these same HIV medicines can cause faster progression of heart disease by raising blood lipids like cholesterol.
“So the question has been, do we start HIV treatment early to treat the virus and help inflammation, with the hope of reducing the risk for heart disease, despite the potential toxicity associated with HIV medicines?”
But in terms of vessel function, the effect of early treatment turned out to be flat.
“At least in patients with preserved immune function and early in the course of [HIV] disease, there was no effect of HIV treatment on vascular measures of heart disease risk,” says Baker, who stresses that this result also means no harm.
He points out that even though treatment showed no benefit for heart disease, the result has one important implication. Fortified with this knowledge, physicians can now speak with more clarity when discussing the implications for heart disease risk, a better situation for patients considering starting HIV treatment.
All patients in START will be recommended to go into therapy and will be followed until the end of 2016. But can this become reality for every HIV-positive person in the world, especially when so many live in isolated or poverty-stricken areas?
“There are enough drugs to do this,” says Neaton. “The question is about having the infrastructure to deliver them, and also the cost. … I think policy-makers will look for ways to get everybody on treatment because it allows them to live longer and reduce the risk of transmission. All over the world, people are noticing this study and reacting.”