Dual Therapy With Raltegravir and Darunavir

The leading U.S. HIV treatment guidelines developed by the U.S. Department of Health and Human Services (DHHS) for adults have several regimens that it recommends from which doctors and their patients can choose for the initial therapy of HIV. These regimens consist of a combination of three active drugs.

In the previous issue of TreatmentUpdate, we presented information about simplified regimens. In this issue, we have a report on one of the largest clinical trials of simplified therapy testing two powerful and generally well-tolerated anti-HIV drugs: darunavir (Prezista) + raltegravir (Isentress). This combination was given to people who had not previously used anti-HIV therapy, and researchers found that after two years dual therapy was roughly as effective as standard triple therapy containing darunavir.

In the years ahead, it will be interesting to see what treatment guideline committees, such as those convened under the aegis of the DHHS, have to say about starting therapy with simplified regimens.

Study Details

Researchers in Europe conducted a clinical trial comparing standard therapy with a simplified regimen of two active drugs for the initial therapy of HIV. The two regimens are as follows:

  • darunavir 800 mg/day + ritonavir (Norvir) 100 mg/day (both drugs once daily) + raltegravir (Isentress) 400 mg twice daily
  • darunavir 800 mg/day + ritonavir 100 mg/day + Truvada (a fixed-dose regimen of two drugs: tenofovir + FTC)

Note that because ritonavir is given at a low dose, its sole purpose is to raise, or boost, levels of the protease inhibitor darunavir. At low doses, ritonavir does not have any significant anti-HIV activity so it is not counted as part of an active regimen. When used with ritonavir, darunavir has very powerful anti-HIV activity.

The other main drug used in this study was raltegravir, the first integrase inhibitor to become available. Raltegravir has powerful anti-HIV activity when used together with boosted darunavir.

Although researchers randomly assigned participants to the study regimens, participants knew which drugs they received; no placebos were used.

In this clinical trial, called NEAT 001/ANRS 143, researchers collected data for at least 96 weeks from participants in 15 countries. The average profile of participants at the start of the study was as follows:

  • 88% men, 12% women
  • HIV viral load: 58,000 copies/ml
  • about 1/3 of participants had a viral load greater than 100,000 copies/ml
  • 6% had a viral load greater than 500,000 copies/ml
  • CD4+ count: 330 cells
  • 5% had AIDS
  • 4% had hepatitis C virus co-infection

Of the 805 participants enrolled, 401 were assigned to receive dual therapy and 404 others to receive standard triple therapy.

Results -- Changes in Viral Load

The proportions of participants whose viral load was less than 50 copies/ml at different points in the study were distributed as follows:

48 weeks

  • dual therapy: 89% had a viral load less than 50 copies/ml
  • triple therapy: 91% had a viral load less than 50 copies/ml

96 weeks

  • dual therapy: 89% had a viral load less than 50 copies/ml
  • triple therapy: 93% had a viral load less than 50 copies/ml

Focus on Virologic Failure

According to the study design, participants who had a viral load in their blood of at least 50 copies/ml at week 32 were considered to have virologic failure. These cases were distributed as follows:

  • dual therapy: 27 cases of virologic failure at the 32nd week of the study
  • triple therapy: 28 cases of virologic failure at the 32nd week of the study

After week 32, additional participants who developed virologic failure were distributed as follows:

  • dual therapy: 32 cases of virologic failure
  • triple therapy: 22 cases of virologic failure

Genotypic resistance testing was done on a sub-group of all participants with virologic failure as follows:

  • dual therapy: 28 participants
  • triple therapy: 13 participants

There was no evidence of HIV developing resistance to protease inhibitors -- the category to which darunavir belongs -- in blood samples from participants on either study regimen.

In five cases researchers found evidence that HIV had developed major mutations against raltegravir.

Effectiveness and Statistics

Prior to launching the study, the researchers developed a complex series of goals by which to assess the effectiveness of each regimen. These were a combination of virologic and clinical results (called endpoints), some of which we report. When the study results were analysed this way, the differences between regimens were relatively small. According to the statistical design that underpinned the study, researchers then declared that, overall, the experimental regimen of raltegravir + darunavir + ritonavir was "non-inferior" to standard triple therapy with darunavir + ritonavir + tenofovir + FTC. This interpretation does not mean that the regimens are equivalent, merely that, overall, the dual therapy in this study was not worse than triple therapy in measures of effectiveness.

Dual therapy was inferior to triple therapy in one regard -- among the sub-group of participants who entered the study having less than 200 CD4+ cells.

Changes in CD4+ Cell Counts

Below are the increased numbers of CD4+ cells that were reported for participants at different time points in the study:

48 weeks

  • dual therapy: 197 more cells/ml
  • triple therapy: 193 more cells/ml

96 weeks

  • dual therapy: 267 more cells/ml
  • triple therapy: 266 more cells/ml

Sub-Group Analyses

An average figure for viral load or CD4+ count at the start of therapy tends to smooth over differences in a large group where people have varying cell counts and viral loads. Thus, sub-group analyses -- which look at sub-groups of people who have low CD4+ counts or high viral loads and analyses trends within these groups -- are important. Below are some of these sub-group analyses.

The CD4+ count that some participants had at the start of the study (baseline) appeared to influence their subsequent response to the study regimens. For instance, there were 123 participants whose CD4+ count at the start of the study was less than 200 cells/ml. Below are the proportions whose treatment failed:

  • dual therapy: 39%
  • triple therapy: 21%

In contrast, among 682 participants who entered the study with a CD4+ count greater than 200 cells/ml, below is how their treatment failures were distributed:

  • dual therapy: 14%
  • triple therapy: 12%

Rates of treatment failure among 275 participants who had a baseline viral load greater than 100,000 copies/ml were distributed as follows:

  • dual therapy: 36%
  • triple therapy: 27%

Rates of treatment failure among participants whose baseline viral load was less than 100,000 copies/ml were distributed as follows:

  • dual therapy: 7%
  • triple therapy: 7%

At the start of the study about 5% of participants had a viral load greater than 500,000 copies/ml.

Among participants whose dual therapy regimens failed, four of five entered the study with a viral load "much greater" than 500,000 copies/ml. Analysis of their blood samples after treatment failure occurred found that in four of these five participants, HIV with mutations that allowed it to resist the effect of integrase inhibitors -- the class to which raltegravir belongs -- was present.

Safety and Tolerability

None of the safety differences between study regimens were statistically significant.

Serious adverse events (SAEs) -- these could be side effects, complications related to HIV or other causes -- are always recorded in a clinical trial and then later analysed to determine if the study drugs played any role in their formation.

Here is the overall distribution of SAEs:

  • dual therapy: 89 events were reported from 79 participants
  • triple therapy: 75 events were reported from 61 participants

Death and Other Serious Events

Here is the distribution of deaths that occurred during the study:

  • dual therapy: four participants died; one death each from lymphoma, a severe drug hypersensitivity reaction, skin cancer, suicide
  • triple therapy: one participant died from overdose of morphine

Very serious events were distributed as follows:

  • dual therapy: eight cases in total, distributed as follows: elevated levels of enzymes in the blood suggestive of muscle breakdown (five cases); one each of liver inflammation, inflammation of the pancreas gland and Hodgkin's lymphoma
  • triple therapy: four cases in total, distributed as follows: elevated levels of enzymes in the blood suggestive of muscle breakdown (two cases); one heart attack and one case of elevated liver enzymes

Less than 1% of participants taking either study regimen had abnormal changes in fatty substances in the blood -- cholesterol and triglycerides. Overall, there were no significant differences between regimens in the important ratio of total cholesterol to HDL-cholesterol.

Focus on the Kidneys

There was a small but statistically significant decrease in kidney health (as assessed by using eGFR -- estimated glomerular filtration rate) among triple-therapy users: eGFR increased by about 4 units. This is in contrast to an increase of 1 unit in eGFR seen among participants taking dual therapy.

These clinically insignificant changes were maintained for 96 weeks and underscore the overall safety of both study regimens for the kidneys.

Overall

According to the study researchers, a regimen of twice-daily raltegravir together with once-daily boosted darunavir was "well-tolerated" and had similar effectiveness as triple therapy with boosted darunavir. However, among participants who entered the study with less than 200 cells/ml, dual therapy with boosted darunavir and raltegravir was inferior to triple therapy.

Overall, the researchers found the safety of both regimens to be similar. They concluded by stating that the combination of raltegravir + boosted darunavir represents an alternative option (to boosted darunavir + Truvada) for first-line therapy, particularly in patients who have more than 200 CD4+ cells/ml.

Bear in Mind

Although the results from NEAT are interesting, it is important to note that leading treatment guidelines, such as ones produced by the DHHS, do not recommend initiating HIV with simplified regimens.

Reference

Raffi F, Babiker AG, Richert L, et al. First-line raltegravir + darunavir-ritonavir is non-inferior to tenofovir-emtricitabine + darunavir-ritonavir: The NEAT 001/ANRS 143 randomized trial.  In: Program and abstracts of the 21st Conference on Retroviruses and Opportunistic Infections, 3-6 March 2014. Abstract 84LB.