Long-awaited results from the START study, released ahead of schedule, show that people with HIV who start treatment early have a significantly lower risk of illness and death than those who wait.
Specifically, people who were randomly assigned to start antiretroviral therapy (ART) while their CD4 T-cell count was above 500 had a 53 percent lower likelihood of AIDS-related and non-AIDS events and deaths compared to those who delayed treatment until their CD4 count fell below 350.
"We now have clear-cut proof that it is of significantly greater health benefit to an HIV-infected person to start antiretroviral therapy sooner rather than later," National Institute of Allergy and Infectious Diseases director Anthony Fauci said in the May 27 announcement. "These findings have global implications for the treatment of HIV."
Other AIDS experts also weighed in.
"The study confirms that starting antiretroviral therapy early and not waiting �" even when people feel well �" is beneficial for an HIV-positive person's health," Dr. Diane Havlir, chief of the Positive Health Program at San Francisco General Hospital, told the Bay Area Reporter. "START provides more data for remaining skeptics about the benefit of early therapy."
Project Inform officials noted that the study findings support existing guidelines.
"Even in San Francisco, which has some of the highest HIV treatment and viral suppression rates in the country, we struggle to get everyone on treatment who needs it," said Project Inform's David Evans. "The START study findings support the long-standing guidelines that early treatment benefits everyone and merits the developing strategies of the city's Getting to Zero campaign."
That campaign's goal is to cut HIV transmissions by 90 percent by 2020.
San Francisco leads the way
Several observational studies have found that starting HIV treatment sooner is associated with better outcomes. But until now the optimal timing of early ART has not been confirmed by randomized, controlled clinical trials �" the "gold standard" for medical evidence.
It is well known that starting treatment before extensive immune system damage reduces disease progression and death. Once the CD4 count falls below 350 �" and even more so below 200 �" people with HIV are susceptible to opportunistic infections and cancers. But chronic HIV infection causes persistent inflammation and immune activation that can lead to problems long before T-cells fall into the danger zone.
However, in addition to its benefits �" which include nearly eliminating the chance of passing the virus on to others �" early HIV treatment also has potential drawbacks such as longer exposure to drug side effects and emergence of drug-resistant virus.
In 2010 San Francisco was the first city to recommend treatment for everyone diagnosed with HIV regardless of CD4 count. U.S. treatment guidelines followed suit in 2013. The World Health Organization currently recommends treatment when the T-cell count falls to 500.
"The 'when to start' debate in San Francisco has been in the rear view mirror for years," Havlir said. "We debated the pros and cons back then, but ultimately recommended early treatment because data were rapidly accumulating to show that early therapy preserves overall health, prevents AIDS complications, and protects against damage to organs such as the heart and brain. The earlier therapy is started the greater the chance to restore the immune system to full capacity and to limit the size of the HIV reservoir in the body."
Doctors at Kaiser agreed.
"START removes any doubt about the benefits of early HIV treatment," Dr. Brad Hare, director of HIV services at Kaiser Permanente, told the B.A.R. "In San Francisco we've been ahead of the game, recommending treatment for everyone, regardless of their CD4 count, since 2010. START confirms this is the right approach. For anyone who has been unsure about starting HIV medications, the results of START show the benefits of starting early."
START design and results
The Strategic Timing of Antiretroviral Treatment study, funded by the U.S. National Institutes of Health and several European agencies, enrolled 4,685 HIV-positive participants in 35 countries worldwide. Nearly three-quarters were men and the average age was 36. At study entry they had CD4 counts in the normal range �" above 500 cells/mm3 �" and most were within their first year after being diagnosed.
Participants were randomly assigned to either start ART immediately or remain off treatment until their CD4 count fell to 350 or they developed an AIDS-defining condition. Nearly half of the deferred group ended up starting treatment, usually due to declining T-cells.
The study, which started in 2009, was scheduled to conclude at the end of 2016. But results were released early after an interim review showed that people who started early ART had about half the risk of reaching a combined endpoint of AIDS-related events (such as opportunistic infections and AIDS-defining cancers), serious non-AIDS events (such as major cardiovascular, kidney, or liver disease or non-AIDS cancers), or death.
As of March 2015, there were 41 cases of AIDS-related events, serious non-AIDS events, or deaths among people randomized to the early treatment group compared to 86 combined events in the deferred treatment group �" a 53 percent reduction. Encouragingly, the benefits of early treatment were similar for participants from low-, middle-, and high-income countries. Serious side effects occurred at about the same rate in both groups.
While it was widely assumed that early treatment would prove beneficial, the magnitude of the effect was unexpected. Also surprising was the fact that AIDS-related events declined even more than non-AIDS events with early treatment, since opportunistic illnesses usually occur at low CD4 counts. Looking at AIDS and death alone, there were 14 cases in the early treatment group compared to 46 in the deferred group �" a 70 percent reduction.
"The results show exactly why the study was needed," said longtime AIDS treatment advocate Simon Collins. "Nobody thought that early treatment would reduce AIDS events at very high CD4 counts."
Although the relative or comparative risk reduction in the early versus delayed treatment groups was impressive, the absolute number of events was low in both groups, given that the study population was quite healthy. Among 100 patients followed for one year, the rate of illness or death fell from 1.25 cases in the early treatment group to 0.6 cases in the deferred group.
Based on these findings, the study's data and safety monitoring board decided to halt the randomized portion of the trial. Everyone initially assigned to the delayed treatment group will now be offered ART. Participants will continue to be followed to monitor long-term outcomes. Further data are expected to be presented at the International AIDS Society conference this summer in Vancouver.
"The results from START are very informative and certainly place more emphasis on treatment to prevent the loss of CD4 cells when they reach 500," said UCSF Professor Jay Levy, who has been a skeptic of very early treatment. "I await the publication of the full study since the question remains as to whether individuals who maintain a CD4 cell count of 500 or above would require immediate therapy. Our clinical cohort has several people with CD4 counts of more than 600 cells. I remain reluctant to begin them on antiviral therapy now."
Guidelines and clinical practice
Although U.S. guidelines already recommend treatment for everyone diagnosed with HIV, the START results will likely influence other countries with more cautious guidelines. Some, like the U.K. with its CD4 threshold of 350, have held off on recommending very early treatment due to lack of evidence, while many low- and middle-income countries have focused their limited resources on people who need treatment most urgently.
"Every person living with HIV should have immediate access to life-saving antiretroviral therapy," UNAIDS Executive Director Michel Sidibe said in response to the findings. "This is a further demonstration of the importance of science and research that enables an evidence-based, people-centered response to HIV that leaves no one behind."
Expanding eligibility will increase the global cost of treatment. According to UNAIDS, only 38 percent of the estimated 35 million people living with HIV worldwide are now on ART. But earlier treatment could ultimately prove cost-effective as it prevents new infections and reduces progression to serious illness.
"The START study will likely have limited impact in San Francisco �" I think everyone here has bought into the idea that although treatment is not benign, it is less harmful than the virus, and most providers are recommending therapy for nearly everyone," UCSF Professor Steven Deeks told the B.A.R. "The same may be true for the entire U.S. I think the main effect will be in parts of Europe, where deferring therapy is still common. Also, it is likely that governments and other institutions that pay for therapy will now be more likely to find the resources to expand coverage."
While most providers in the U.S. may recommend prompt treatment for their patients, the Centers for Disease Control and Prevention estimates that of the 1.2 million people living with HIV in the U.S., about 14 percent remain undiagnosed and only 37 percent have been prescribed ART.
Although the START findings may not change practice locally, they support the goals of San Francisco's Getting to Zero plan for eliminating new HIV infections. Starting antiretroviral therapy as soon as people are diagnosed is part of the three-pronged approach, along with pre-exposure prophylaxis, also known as PrEP, and improving retention in care.
"In our Getting to Zero plan we are bringing the city together to use HIV therapy for prevention and to insure that those with new HIV infections are rapidly offered treatment and support and engaged and maintained in care," said Havlir. "The focus has changed from 'when should we offer treatment?' to 'how can we most effectively deploy treatment?'"
One AIDS expert said the major question, not surprisingly, is who will fund expanded treatment.
"I didn't think [START] was a necessary trial as we've know for a long time that all should be treated for their own health and to stop transmission," UCSF Center for AIDS Research director Paul Volberding told the B.A.R. "But policymakers do notice results like this. Hopefully, it will change the discourse from 'when to start?' to 'who will pay?'"