TreatmentUpdate
224

January 2018 

Dolutegravir + rilpivirine as maintenance therapy

In two large randomized studies, called Sword-1 and Sword-2, researchers assigned more than 1,000 HIV-positive participants who were taking ART and who had an undetectable viral load to receive one of the following regimens:

  • dolutegravir 50 mg + rilpivirine 25 mg (both drugs with a meal)
  • continued use of their current ART regimen (CAR)

After 48 weeks, 95% of participants in both regimens had a viral load that was less than 50 copies/mL. Statistically, this demonstrates that dolutegravir-rilpivirine was no worse than (the technical term for this is non-inferior) standard ART when used as maintenance therapy. Most side effects reported by participants taking dolutegravir-rilpivirine were mild and the combination was generally safe.

The combination of dolutegravir-rilpivirine will be co-formulated into one pill and will likely be approved in Canada and the European Union later this year and sold under the brand name Juluca.

Study details

People recruited for this study were on their first or second combination, did not have a detectable viral load in the past six months, and did not have HIV that was significantly resistant to the main classes of commonly used treatments (nukes, non-nukes, protease inhibitors, integrase inhibitors). They also had never changed their initial regimen because of virological failure. According to the researchers, no one “at substantial risk of suicide” was allowed to participate and no one with hepatitis B virus co-infection was allowed into the study, as neither dolutegravir or rilpivirine have any activity against this virus.

The average profile of participants upon entering the study was as follows:

  • age – 43 years
  • 78% men; 22% women
  • major ethno-racial groups: white – 80%; black – 8%; Asian – 9%; Indigenous – 3%
  • CD4+ cell count – 600 cells/mm3
  • viral load – less than 50 copies/mL

Prior to randomization, commonly used regimens included the following:

  • efavirenz + Truvada (TDF + FTC)
  • raltegravir (Isentress) + Truvada
  • darunavir (Prezista) + ritonavir + Truvada

The week 48 results were recently published.

Results

As participants entered the study with viral loads already suppressed, researchers were interested in how many continued to remain suppressed by the 48th week of the study. The proportions were as follows:

  • dolutegravir-rilpivirine – 95%
  • CAR – 95%

Statistically, this shows that dolutegravir-rilpivirine was no worse than, or non-inferior to, standard ART.

The actual proportions of participants who did not achieve virological suppression were low—about 1% of people on both regimens. The remaining 4% of participants on each regimen did not appear in the final analysis of viral loads at week 48 because they had withdrawn from the study for a variety of reasons.

Increases in CD4+ cell counts were modest and distributed as follows:

  • dolutegravir-rilpivirine – an increase of 28 cells/mm3
  • CAR – an increase of 22 cells/mm3

Safety

Overall, researchers found that more drug-related adverse events were reported by participants taking dolutegravir-rilpivirine than standard ART. They were distributed as follows:

Headache

  • dolutegravir-rilpivirine – 2% of participants
  • CAR – zero participants

Diarrhea

  • dolutegravir-rilpivirine – 2% of participants
  • CAR – less than 1% of participants

Focus on the mind

The researchers said that “most neuropsychiatric events” reported in the study were of mild-to-moderate intensity. Furthermore, they did not consider the majority of such events to be related to dolutegravir-rilpivirine or CAR. They said that neuropsychiatric events “often occurred in participants with a history of anxiety, depression or insomnia.”

Here is the overall distribution of psychiatric disorders that occurred in the study. According to the researchers, these were not related to the study medicines:

  • dolutegravir-rilpivirine – 12%
  • CAR – 6%

The reason that such disorders were doubled in participants receiving dolutegravir-rilpivirine is unclear and was not explained by researchers. That the rate of these disorders was 6% among people who took CAR suggests that such problems are relatively common. This should not be surprising, as other studies have found higher rates of mental health issues among HIV-positive people.

In contrast to the previous distribution, here is the distribution of common neuropsychiatric problems that researchers determined were related to the study medicines:

Sleeping problems

  • dolutegravir-rilpivirine – 3% of participants
  • CAR – 2% of participants

Anxiety

  • dolutegravir-rilpivirine – 2% of participants
  • CAR – 2% of participants

Depression

  • dolutegravir-rilpivirine – 3% of participants
  • CAR – 1% of participants

Abnormal dreams

  • dolutegravir-rilpivirine – 1% of participants
  • CAR – zero participants

The number of people who left the study prematurely due to bothersome neuropsychiatric problems was distributed as follows:

  • dolutegravir-rilpivirine – seven people
  • CAR – one person

Thus, around 1% of participants left the study prematurely because of these problems when they were taking dolutegravir-rilpivirine.

One person taking dolutegravir-rilpivirine had thoughts of suicide and one person on CAR attempted suicide.

Both dolutegravir and rilpivirine can penetrate into the brain. On one hand, this is good because HIV-infected cells of the immune system travel to the brain and some of them, particularly macrophages and related-cells, spend an extended period of time there. On the other hand, if high concentrations of these drugs accumulate in the brain, there is the potential for side effects in some people. The researchers said that the rate of neuropsychiatric side effects in the present study was similar to that seen in other studies of dolutegravir. They therefore do not think that rilpivirine caused additional neuropsychiatric side effects when used with dolutegravir. There will be more information on mental health issues and dolutegravir later in this report.

Lab tests

Inflammation and dolutegravir-rilpivirine

HIV infection causes elevated levels of inflammation; this is partially reduced by ART. However, the level of inflammation in ART users never falls to the very low levels seen in healthy HIV-negative people. According to the study researchers, “there was no consistent pattern of change” when it came to assessments of proteins associated with inflammation, such as IL-6 (interleukin-6) and C-reactive protein (CRP). Overall, this suggests that inflammation levels in participants were stable.

Lipids and sugar

Dolutegravir-rilpivirine had no significant effect on fasting lipid levels—total cholesterol, levels of bad (LDL-C) and good cholesterol (HDL-C), cholesterol ratios and triglycerides.

There was a very small increase in fasting blood sugar levels among participants who took CAR vs. dolutegravir-rilpivirine.

Satisfaction and adherence

Researchers surveyed participants at different points in the study about their satisfaction with their regimens. They found that bothersome symptoms decreased significantly over time among participants taking dolutegravir-rilpivirine vs. symptoms associated with CAR.

Participants reported generally high rates of adherence to their regimens, around 98%.

Bear in mind

The data from Sword-1 and Sword-2 show that the combination of dolutegravir-rilpivirine will likely find a role as maintenance therapy for some, perhaps many, HIV-positive people.

Notes on mental health

Dolutegravir-rilpivirine will not be for everyone. For instance, the researchers said that they screened out potential participants at “substantial” risk for suicide from entering Sword-1 and Sword-2. Note that a small proportion of participants (1%) left the study due to neuropsychiatric effects of dolutegravir-rilpivirine, usually problems related to sleep, anxiety and/or depression. The researchers said that problems related to sleep, anxiety and/or depression “often” occurred in people with a history of such problems when they took dolutegravir-rilpivirine. Their use of the word “often” suggests that some people in this clinical trial who developed neuropsychiatric problems while on dolutegravir-rilpivirine did not have a history of such problems. Precisely why these problems occurred is not clear and requires further research. Other studies have found relatively high rates of mental health issues among people with HIV infection regardless of the type of medicines used.

Clinical trials of all medicines usually enroll participants who are relatively healthy compared to people with the same conditions in the community. Once dolutegravir-rilpivirine gets approved and subsidized by public and private insurance formularies, it is likely that a somewhat different profile of people in the community will receive these drugs compared to those in Sword-1 and Sword-2. As a result, the rates of side effects reported in the community may be greater than what was reported in clinical trials. A rough estimate for HIV drug development is that the rate of bothersome side effects will likely be about two- or three-fold greater in the average person in the community than what was reported in pivotal clinical trials. This has been the case with reports of neuropsychological side effects associated with dolutegravir compared to results from the pivotal clinical trials that were used for the approval of this drug. Thus, between 2% and possibly up to 6% of people who use dolutegravir-rilpivirine in the community may experience problems related to sleep, anxiety and/or depression possibly caused by dolutegravir-rilpivirine.

The good news is: Based on this rough estimate, it is likely that among the vast majority of people who use dolutegravir or dolutegravir-rilpivirine such side effects should not occur.

—Sean R. Hosein

REFERENCES:

  1. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018; in press.
  2. Boyd MA, Cooper DA. Combination ART: are two drugs as good as three? Lancet. 2018; in press.