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Dolutegravir vs. Darunavir for the Initial Treatment of HIV

December 2013

Darunavir (sold as Prezista) belongs to the class of HIV drugs called protease inhibitors. Darunavir is taken with a small dose of another protease inhibitor, ritonavir (Norvir), as ritonavir boosts darunavir levels in the blood so that once-daily dosing is possible. Taken this way, darunavir is a potent anti-HIV drug and an important part of treatment regimens for many HIV-positive people.

Researchers in the U.S and Europe conducted a study called Flamingo to assess the impact of dolutegravir-based combination therapy in the initial treatment of HIV infection. The comparison treatment in Flamingo was darunavir + ritonavir + two nukes (nucleoside analogues).

Results after one year suggest that both dolutegravir- and darunavir-based regimens are effective and generally safe. Dolutegravir-based regimens were found to be statistically superior to darunavir-based regimens. The implications of this and other findings are discussed later in this report.


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Study Details

Researchers analysed health-related data collected from HIV-positive participants who had never previously been treated and randomly assigned them to receive one of the following regimens once daily:

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

Distribution of nukes used:

Flamingo is expected to continue for several years. We now report results from the first 48 weeks of the study.


Results

At week 48, the proportions of participants with a viral load less than 50 copies/ml were as follows:

As a greater proportion of dolutegravir users had a low viral load at week 48, researchers judged dolutegravir to be "statistically" superior to darunavir.

We will explore the implications of this finding of statistical superiority as well as side effects later in this report.


Results by Initial Viral Load

Researchers analysed the data by the initial (baseline) viral load that participants had when they entered the study.

Among participants whose baseline viral load was high (more than 100,000 copies/ml), here are the proportions that had a viral load less than 50 copies/ml at week 48:

Among participants whose baseline viral load was less than 100,000 copies/ml, here are the proportions with less than 50 copies/ml at week 48:

Another way to examine the results is to look at the nukes used, as follows:

Kivexa

Truvada


Changes in CD4+ Cell Counts

Increases in CD4+ counts were similar between dolutegravir and darunavir users. On average, participants' counts increased by 200 more cells at week 48.


Resistance and Virological Failure

Two participants in each treatment group initially suppressed their viral load below the 50 copy/ml mark, but then their viral load became greater than 200 copies/ml after week 24 of the study.


Side Effects and Complications

Here are some common side effects and their distribution:

Diarrhea

Nausea

Headache

The presence of any side effect of moderate-to-severe intensity was distributed as follows:

Here is the distribution of severely abnormal lab tests:

Cholesterol

LDL-C (so-called bad cholesterol)

ALT (alkaline aminotransferase; a liver enzyme)

Creatine kinase (an enzyme, elevated levels of which may be suggestive of muscle breakdown)

No deaths occurred because of the study drugs.


Why Did Statistical Superiority Occur?

Dolutegravir has powerful anti-HIV activity but so does darunavir when boosted with a small dose (100 mg) of ritonavir. Furthermore, the proportion of participants who did not respond virologically to therapy was similar and was distributed as follows:

In part, what appeared to drive the differing overall virological outcomes between the two regimens at week 48 was the number of participants who left the study prematurely. These participants were distributed as follows:

In clinical trials, participants leave a study prematurely for reasons such as adverse reactions (side effects, complications), death, because they moved and so on. Since the study drugs were not lethal and few patients changed residence, researchers were able to focus on adverse reactions as a reason for premature withdrawal from the study, distributed as follows:

These findings suggest that dolutegravir-based regimens were likely easier to tolerate.

One question that does not have a clear answer is this:

Does statistical superiority mean that dolutegravir is clinically superior to darunavir?

Boosted darunavir remains an important treatment option and may be a more forgiving regimen (requiring the development of multiple resistance mutations before treatment failure occurs), as is generally the case with other boosted protease inhibitor regimens. Yet, dolutegravir's potency and relative simplicity (the lack of boosting) may make it an attractive option for some doctors and their patients.


In the Future

A once-daily pill containing the following three medicines is under development: dolutegravir + abacavir + 3TC.


Reference

Feinberg J, Clotel B, Khuong M-A, et al. Once-daily dolutegravir (DTG) is superior to darunavir/ritonavir (DRV/r) in antiretroviral-naïve adults: 48-week results from Flamingo (ING114915). In: Program and abstracts of the 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy, 10-13 September 2013, Denver, Colorado, U.S. Abstract H-1464a.




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