March/April 2014 

Comparing the tolerability and effectiveness of initial therapy

Commonly used combinations for initial therapy of HIV can include the following:

  • atazanavir (Reyataz) + low-dose ritonavir (Norvir) + Truvada (tenofovir + FTC)
  • raltegravir (Isentress) + Truvada
  • darunavir (Prezista) + low-dose ritonavir + Truvada

Researchers across the U.S. conducted a large study to compare the effects of these three regimens. They randomly assigned participants to receive one of the three regimens and monitored them for at least 96 weeks. As there were nearly 600 participants per regimen, the study was statistically robust and could determine if the regimens were equivalent, inferior or superior to each other.

Researchers concluded that, overall, each of the study regimens had equivalent virologic effectiveness. The atazanavir-containing regimen was not tolerated as well as the other two regimens. When researchers sought to analyse and compare each of the regimens for their combined effectiveness and tolerability, a raltegravir-based regimen was superior to the other two. Furthermore, a regimen of boosted darunavir was superior to that of boosted atazanavir when assessed by the combined endpoint of tolerability and effectiveness.

Study details

Researchers recruited 1,808 HIV-positive participants and assigned them as follows:

  • boosted atazanavir-containing regimen – 605 people
  • raltegravir-containing regimen – 603 people
  • boosted darunavir-containing regimen – 601 people

The average profile of participants at the start of the study was as follows:

  • 76% men, 24% women
  • age – 37 years
  • HIV viral load – 40,000 copies/ml   
  • distribution of viral loads: 70% of participants had less than 100,000 copies/ml; 23% had between 100,000 to 500,000 copies/ml; 7% had more than 500,000 copies/ml
  • CD4+ count – 308 cells/ml
  • 30% of participants had less than 200 CD4+ cells/ml

Results—Week 96

Rates of virologic failure were similar when comparing all three regimens and were distributed as follows:

  • boosted atazanavir-containing regimen – 13%
  • raltegravir-containing regimen – 10%
  • boosted darunavir-containing regimen – 15%

Statistical analysis found that all three regimens were equally effective at suppressing HIV.

According to researchers, virologic failure accompanied by detectable resistance was “rare” and distributed as follows:

  • boosted atazanavir-containing regimen – 2%
  • raltegravir-containing regimen – 3%
  • boosted darunavir-containing regimen – less than 1%

Another way to assess the results was to compare the proportion of participants who were still on their assigned regimens at week 96 and whose viral load was less than 50 copies/ml:

  • boosted atazanavir-containing regimen – 63%
  • raltegravir-containing regimen – 80%
  • boosted darunavir-containing regimen – 73%

The lower figure for participants taking atazanavir were driven by participants who were originally assigned atazanavir and later changed their regimen, mostly due to toxicity.


The proportion of participants in each regimen who developed side effects that they found intolerable and therefore quit their regimen was distributed as follows:

  • boosted atazanavir-containing regimen – 16%
  • raltegravir-containing regimen – 1%
  • boosted darunavir-containing regimen – 5%

Based on these tolerability results, statistical tests revealed the following:

  • the raltegravir-containing regimen was superior to the atazanavir-based regimen
  • the raltegravir-containing regimen was equivalent to the darunavir-based regimen
  • the darunavir-containing regimen was superior to the atazanavir-based regimen

A combined analysis

Prior to the start of the study, researchers had developed what they called a composite endpoint—essentially this was assessing the regimens due to cumulative failures caused by tolerability or detectable viral load. Using this composite endpoint, statistical analysis revealed the following:

  • the raltegravir-containing regimen was superior to the boosted-darunavir or boosted-atazanavir regimen
  • the boosted-darunavir regimen was superior to boosted atazanavir

These findings were driven by the tolerability issues among atazanavir users. Specifically, the most common reason for participants to discontinue taking atazanavir was because of severe or very severe yellowing of the skin and whites of the eyes (jaundice). This was due to an increase in the waste product bilirubin in their blood, caused by atazanavir. This increase in bilirubin, called hyperbilirubinemia, is not harmful but can be annoying for some people.

Changes in CD4+ counts

At the 96-week mark, here are the increased number of CD4+ cells/ml that were distributed by regimen:

  • boosted atazanavir-containing regimen – 284 more cells/ml
  • raltegravir-containing regimen – 288 more cells/ml
  • boosted darunavir-containing regimen – 256 more cells/ml

These differences are not clinically meaningful.

The researchers affiliated with this study made the following conclusions:

  • All three regimens are virologically equivalent.
  • Boosted atazanavir is not as well tolerated as the other regimens.
  • Raltegravir was superior to the other regimens when taking into account its tolerability and antiviral activity.
  • Boosted darunavir was superior to boosted atazanavir when taking into account its tolerability and antiviral activity.

It is not over

Further analyses of the data from this study are underway. Such sub-studies will yield information about the impact of different treatments on the following (or in some cases, vice versa):

  • cardiovascular health
  • metabolic issues
  • bone density
  • inflammation
  • adherence
  • gender

—Sean R. Hosein


Landovitz RJ, Ribaudo HJ, Ofotokun I, et al. Efficacy and tolerability of atazanavir, raltegravir or darunavir with emtricitabine-tenofovir: ACTG A5257.  In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014. Abstract 85.