A pill containing two anti-HIV drugs -- dolutegravir + rilpivirine -- has been approved for use in Canada, the European Union and the United States. This pill is sold under the brand name Juluca and is meant to be used as maintenance treatment. With maintenance treatment, a patient first has their HIV viral load suppressed with a standard combination of three- or four-drug regimens (this is sometimes called induction therapy). Once their viral load has been suppressed (less than 50 copies/mL) and stays suppressed, their doctor may offer to replace their current regimen with a simplified regimen of the two drugs in Juluca.
In clinical trials called Sword 1 and Sword 2, researchers tested a combination of dolutegravir + rilpivirine in more than 1,000 participants for up to two years. At the end of this time, 89% of participants taking Juluca had a viral load less than 50 copies/mL, attesting to the combination's power and tolerability.
The 48-week results from Sword 1 and Sword 2 were previously reported here.
In this issue of TreatmentUpdate, we largely focus on results after week 52.
The data from Sword 1 and Sword 2 were pooled for the present analysis, as the two trials were identical in design.
Participants who had been taking potent combination anti-HIV therapy (ART) and had a viral load less than 50 copies/mL on standard three- or four-drug regimens were randomly assigned to receive one of the following interventions:
- Juluca, one pill taken once daily with food -- 513 people
- continue their current anti-HIV regimen (CAR) for the first 52 weeks of the study, then switch to Juluca -- 511 people
After 52 weeks in the study, participants who were still on standard ART had their regimens switched to Juluca. Thus, from week 52, everyone in the study was taking Juluca. All participants will be monitored for a total of 144 weeks, but the current analysis provided data for the first 100 weeks of the study.
The average profile of participants upon entering Sword 1 or Sword 2 was as follows:
- age -- 43 years
- 22% females, 78% males
- major ethno-racial groups: white -- 80%; black -- 8%; Asian -- 9%; Indigenous -- 3%
- CD4+ count -- 600 cells/mm3
- viral load -- less than 50 copies/mL
Commonly used regimens before participants were randomized to the study regimens included the following:
- Atripla (efavirenz + tenofovir DF + FTC)
- raltegravir (Isentress) + Truvada (tenofovir DF + FTC)
- darunavir (Prezista) + ritonavir + Truvada
As participants entered the study with undetectable viral loads (less than 50 copies/mL), researchers were interested in the proportions of participants who maintained this suppression:
- Juluca taken week 1 to 100 -- 89%
- Juluca taken week 52 to 100 -- 93%
These differences in the proportions of participants with a suppressed viral load were not statistically significant. Thus, Juluca is considered similarly effective as maintenance treatment compared to standard triple therapy.
The proportions of participants whose regimens were never able to get below the 50-copies/mL mark (this was considered "virological failure" by the researchers) were as follows:
- Juluca taken week 1 to 100 -- 13 people (3%)
- Juluca taken week 52 to 100 -- 10 people (2%)
Analysis of stored blood samples suggested that in some cases where virological failure occurred, participants had entered the study with HIV that had partial resistance to dolutegravir or rilpivirine.
Some participants' data were not available for the analysis at the 100-week mark because they had left the study for a variety of reasons, such as treatment failure, personal choice, side effects, change in residence, pregnancy, and so on.
Complications and Side Effects
The term adverse events is used by researchers to describe a range of unfortunate events that can occur to people in a clinical trial. Those events may be caused by drug side effects, the underlying disease process or circumstances outside of the clinical trial.
Common general side effects in participants taking Juluca were nausea (2%) and headache (2%). These were generally mild and temporary.
The proportions of participants who left the study because of bothersome side effects were as follows:
- Juluca taken week 1 to 100 -- 7%
- Juluca taken week 52 to 100 -- 3%
Focus on the Brain
The drugs inside Juluca -- dolutegravir + rilpivirine -- can enter the brain. This is good because there are HIV-infected cells in the brain. However, a downside is that these drugs can sometimes have side effects that can affect a person's mood and sleep. The proportions of participants who left the study prematurely because of brain-related side effects were distributed as follows:
- Juluca taken week 1 to 100 -- 34 people (7%)
- Juluca taken week 52 to 100 -- 15 people (3%)
Specific brain-related adverse effects that led to some participants leaving the study prematurely were distributed as follows:
Juluca taken week 1 to 100
- anxiety -- 4 people
- related to depression -- 4 people
- thoughts of self-harm -- 4 people
- sleeping problems -- 2 people
- nightmares -- 1 person
- committed suicide -- 1 person
Juluca taken week 52 to 100
- sleeping problems -- 3 people
- related to depression -- 3 people
- confusion -- 1 person
- loss of libido -- 1 person
- "diminished motivation" -- 1 person
- thoughts of suicide -- 1 person
Due to the study design, it is not clear what proportion of neuropsychiatric events were caused by exposure to Juluca between week 52 and 100. However, a look at the 48-week results from the trial may be useful in assessing the distribution of mental health side effects.
Analysis of Blood and Urine Tests
Low-dose X-ray scans (called DEXA) are the gold standard for assessing bone mineral density. However, in the present studies, rather than using DEXA, researchers assessed levels of certain proteins in the blood that are associated with changes in bone density. They found that, overall, Juluca likely had a neutral effect on bones.
Blood and urine tests suggested a modest improvement in kidney health over the course of the study.
Lipids -- cholesterol and triglycerides
Juluca did not appear to have a significant impact on changes in lipid levels in the blood.
For the Future
The results from Sword 1 and Sword 2 are promising. They suggest that maintenance therapy with Juluca is possible and can be successful in many patients. Clinical trials with Juluca will continue until week 144.
Aboud M, Orkin C, Podzamczer D, et al. Durable suppression 2 years after switch to dolutegravir + rilpivirine 2-drug regimen: SWORD-1 and SWORD-2 studies. In: Program and abstracts of the 22nd International AIDS Conference, 23-27 July 2018, Amsterdam, Netherlands, poster THPEB047.
[Note from TheBodyPRO: This article was originally published by CATIE on Dec. 7, 2018. We have cross-posted it with their permission.]