Study heralds an important shift in care and treatment

Historically, decisions about when to start potent anti-HIV combination therapy (commonly called ART) have centred on different CD4+ cell count levels (or thresholds) in the blood. These thresholds were developed as doctors sought to balance the benefit of treatment with the risks of side effects. Finding such a balance was particularly important, as older combinations of anti-HIV drugs tended to have many side effects and involved taking several pills several times daily.

In 2015, the leading treatment guidelines in the U.S. greatly simplified choices for the initial treatment of HIV. These choices are fewer and clearer—the initial combination in a regimen should be based on a backbone of either an integrase inhibitor or the protease inhibitor darunavir (Prezista).

Integrase inhibitors are generally safe and well tolerated and can quickly reduce HIV levels in the blood when used as part of combination therapy. Darunavir-based therapy has been available for nearly 10 years in high-income countries and is potent and generally well tolerated.

About CD4+ cells

A key blood test for monitoring the overall health of the immune system is the CD4+ cell count. This is the number of CD4+ cells in a drop (or cubic mm) of blood. In general, in HIV infection, the greater the number of CD4+ cells, the better. In another report in this issue of TreatmentUpdate, we discuss other issues related to the CD4+ count, such as researchers interpreting new data about what the normal range should be.

A shifting threshold

As mentioned earlier, discussions about starting ART have usually centred on the CD4+ count. Historically, treatment was usually deferred until the CD4+ count fell and defects in the immune system caused by HIV infection resulted in a high risk for developing serious infections and cancers—the hallmark of AIDS.

However, over the past 15 years the recommended threshold for initiating ART has been climbing, from a low of 200 cells/mm3 to 350 cells to 500 cells and, in the latest version of U.S. government guidelines, immediate therapy regardless of CD4+ count.

The U.S. guidelines are produced under the aegis of that government’s federal health ministry, the Department of Health and Human Services (DHHS). Over the past several years, guidelines from the DHHS have been encouraging earlier initiation of ART. This shift was based on emerging research in two important areas:

  • how HIV harms the immune system well before CD4+ counts fall significantly
  • how ART can lower viral load in the blood below 50 or 40 copies/ml (depending on the test used) and, as a result, significantly reduce the risk of sexual transmission of HIV

Now, a detailed report from START, a large and well-designed clinical trial that ran for several years, provides robust evidence for starting ART soon after HIV diagnosis.

A summary of START

The results from START show that HIV-positive people who are not taking ART and whose CD4+ cell counts were greater than 500 cells/mm3 (a threshold sometimes considered the lower end of the normal range) are at significantly increased risk for developing life-threatening infections, cancers and cardiovascular complications compared to other HIV-positive people with similar CD4+ counts who started ART relatively early in the course of HIV disease. Furthermore, serious side effects in START were rare, occurring in less than 1% of participants.

The START results are robust and mark a major achievement in medicine:

  • They underscore the dangerous consequences of untreated HIV disease, even in people with relatively high CD4+ cell counts who had only been infected a relatively short time.
  • They highlight the need for more research about how HIV harms the immune system.
  • They confirm the power, effectiveness and safety of ART.

For the future

If the benefits flowing from START are to be realized, more opportunities for HIV testing need to be made available. Also, the healthcare system will require further integration so that people who test positive for HIV can be swiftly referred for care, counselling and an offer of treatment.

Of course, newly diagnosed patients will need support and education about the benefits of early ART and how HIV disease can be managed. As well, counselling from a nurse or pharmacist about adherence (the ability to take medicines as prescribed every day) as well as practising medication-taking (some doctors, nurses and pharmacists use small candies such as Smarties for this purpose) for a few weeks prior to starting ART may be necessary.

Furthermore, clinics and hospitals need to be vigilant to ensure that HIV-positive patients under their care are able to take ART every day as directed so that their viral load reaches low levels (commonly called “undetectable”) as soon as possible and remains there.

The next report deals with detailed results from START.

—Sean R. Hosein


Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: