Co-authored by Alicen B. Spaulding, Ph.D., M.P.H.
The question of when to initiate antiretroviral therapy (ART) during the course of HIV infection has been debated for years, yet a conclusive answer has remained elusive. For HIV-infected individuals the primary question was whether to start ART early, risking possible cumulative drug toxicities, potential viral resistance, and difficulties with long-term adherence, or to defer ART until later in the course of infection and risk developing irreparable immune system dysfunction or other health issues related to ongoing, uncontrolled HIV replication. For health systems with limited funds, a key question was whether the scientific data justified dedicating the resources required to provide early ART to all HIV-infected individuals. New data are now available to help answer these important questions.
An independent data and safety monitoring board (DSMB) met recently to review preliminary, interim results from March 2015 from an ongoing clinical trial known as the Strategic Timing of AntiRetroviral Treatment (START) study. The START trial, which began in 2009, enrolled 4,685 adults living with HIV infection in 35 countries. Participants were randomly assigned to begin ART immediately (when their CD4+ T cell count -- a measure of immune health commonly referred to as the CD4 count -- was greater than 500 cells per microliter of blood, the "early ART" arm), or to defer ART (when their CD4 count dropped below 350, the "deferred ART" arm). This study was primarily funded by the National Institute of Allergy and Infectious Diseases, a component of the National Institutes of Health (NIH), along with a number of other NIH Institutes and other partners.
The DSMB reported that the accumulated START trial data overwhelmingly support starting ART immediately and recommended that the results be released early. Participants in the early ART arm had a 53 percent lower risk of a primary outcome (defined as AIDS-related illness, serious non-AIDS illness, or death) compared to those who deferred ART. This finding is critical information for the care and treatment of people living with HIV for a number of reasons.
The benefits of ART are well-documented: by suppressing HIV replication, ART has been shown in many studies and in "real world" situations to improve the health and longevity of people living with HIV. While data from clinical trials support initiation of ART at CD4 counts less than 350, only observational studies and expert opinion have been available to support recommendations of initiating ART at CD4 counts higher than 350.
Because of the prevailing clinical impression that ongoing HIV replication has substantial direct and indirect deleterious effects not only on the immune system, but also on other organ systems, some healthcare workers, especially in resource-rich settings, had begun offering ART to individuals with CD4 counts higher than 350. However, clinical impressions in the absence of appropriate controls can be misleading, and a randomized trial was needed to provide conclusive evidence that the benefits of early ART outweighed the risks.
The START trial provides this evidence and the impact will be considerable. For individual patients and their health care providers, the new data provide reassurance that a decision to start ART earlier rather than later is backed by solid scientific evidence. More broadly, treatment recommendations for HIV-infected people will now need to be re-examined in light of this new information. International guidelines from the World Health Organization issued in 2013 recommended ART for all HIV-infected individuals based on expert opinion and, in particular, strongly recommended ART for people with CD4 counts between 350 and 500 based largely on nonrandomized trials and observational cohort studies. Similarly, guidelines issued in 2014 by the Department of Health and Human Services also recommended ART for all HIV-infected individuals based on expert opinion to reduce the risk of disease progression and, in particular, strongly recommended ART for those with CD4 counts between 350 and 500 based on nonrandomized trials and observational cohort studies. The START trial now adds an entirely new dimension of scientific evidence to inform future recommendations for the initiation of ART in HIV-infected individuals.
Starting ART early can offer a number of potential benefits. It has a clearly positive impact on the health of the infected individual, and can also substantially reduce the risk of transmission of the virus to uninfected sexual partners. In this regard, the new data from the START trial strengthen the rationale for "treatment as prevention" programs, providing strong evidence that early ART will benefit the HIV-infected individual in addition to proven effects of reducing the risk of HIV transmission to uninfected sexual partners. Early initiation of ART also can help close a critical gap in the continuum of care for an infected person, or the path from diagnosis to virologic suppression. It is estimated that more than 60% of HIV-infected people in the U.S. are lost to follow-up between the establishment of a diagnosis of HIV infection and the initiation of ART. Starting therapy closer to the time of diagnosis may help close this gap.
Thirty-five million people are currently living with HIV around the world and in 2013 alone 2.1 million people were newly infected with HIV. Although the START trial now provides firm scientific proof of the benefits of early initiation of ART, to achieve full viral suppression for all HIV-infected individuals will require addressing a number of care and treatment challenges including stable access to medications, access to trained healthcare workers, and achieving the high levels of adherence required for ART effectiveness.
Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health and Chief of the NIAID Laboratory of Immunoregulation. Alicen B. Spaulding Ph.D., M.P.H., is an epidemiologist and NIH Presidential Management Fellow on rotation in the NIAID Immediate Office of the Director.