Dolutegravir + rilpivirine fixed-dose combination (Juluca): new antiretroviral available on PBS

• Fixed-dose combination (FDC) of dolutegravir + rilpivirine is PBS-listed for people with HIV who are virologically suppressed on a stable antiretroviral regimen for at least 6 months.
  
• There’s growing evidence that two-medicine combinations can maintain viral suppression in people with HIV who have been taking a three-medicine combination.
  
• Guidelines recommend dolutegravir + rilpivirine FDC as a reasonable option for switching people with HIV viral suppression when combinations including nucleoside reverse transcriptase inhibitors are not desirable.
  
• Dolutegravir + rilpivirine FDC should not be given to people with HIV who are resistant to either medicine, who have chronic hepatitis B infection or who are taking proton pump inhibitors.
  
• Dolutegravir has been associated with increased risk of neural tube defects in infants, which has led to the recommendation not to prescribe it for some women.
  

On 1 December 2018, an FDC of dolutegravir + rilpivirine (Juluca) was listed on the PBS as an Authority required (streamlined) listing.

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended that dolutegravir + rilpivirine FDC be listed under the Section 100 – Highly Specialised Drugs Program (Community Access) for people with HIV infection who meet the following criteria.¹

• They must be virologically suppressed on a stable antiretroviral regimen for at least 6 months.
  
• The treatment must be their sole PBS-subsidised therapy for this condition.
  

The PBAC considered dolutegravir + rilpivirine FDC to be similarly effective and as safe as:²

• tenofovir disoproxil fumarate + emtricitabine + elvitegravir + cobicistat FDC (Stribild) or
  tenofovir disoproxil fumurate + emtricitabine + rilpivirine FDC (Eviplera) for most patients
  
• tenofovir alafenamide + emtricitabine + rilpivirine FDC (Odefsey) or
  tenofovir alafenamide + emtricitabine + elvitegravir + cobicistat FDC (Genvoya) for patients with renal impairment who cannot use Stribild or Eviplera.
  

Dolutegravir + rilpivirine FDC is an oral tablet that contains two antiretroviral medicines:^1,3 

• dolutegravir 50 mg and 
  
• rilpivirine 25 mg.
  

Dolutegravir is an integrase strand transfer inhibitor (INSTI) that prevents HIV replication by stopping HIV DNA from integrating into the nucleus of the host cell.^4,5

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that reduces HIV replication by binding directly to the HIV reverse transcriptase enzyme and blocking its RNA-dependent and DNA-dependent polymerase activity.⁴

Dolutegravir + rilpivirine FDC was TGA-registered in June 2018.¹

Dolutegravir + rilpivirine FDC is a recommended option if prescribers are considering switching from a three-medicine combination to a two-medicine combination for people with HIV viral-suppression.^1,6-8

This guidance comes from US Department of Health and Human Services (DHHS) Guidelines for the use of Antiretroviral Agents in Adults and Adolescents Living with HIV⁶ and European AIDS Clinical Society (EACS) Guidelines.⁷ The latest updates of these guidelines were released in October 2018.¹

These recommendations are supported by the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) Antiretroviral Guidelines: US DHHS Guidelines with Australian commentary,⁸ which provide additional guidance for Australian health professionals.

The ASHM commentary is updated after the release of updates to the US DHHS guidelines. The current version is consistent with both the US DHHS and EACS guidelines on the use of dolutegravir + rilpivirine FDC.^6-8

Initiating antiretroviral therapy for treatment-naïve people with HIV

Dolutegravir + rilpivirine FDC is not recommended or PBS-subsidised when initiating antiretroviral therapy (ART) for treatment-naïve people with HIV.^1,6-8

A three-medicine combination, consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and a third antiretroviral medicine, is recommended for most people with HIV.^6,7

The choice of the third medicine is guided by the combination’s expected efficacy, barrier to drug-resistance mutations, safety profile and drug–drug interactions, as well as patient convenience, comorbidities and concomitant medicines.⁶

Switching medicine combination for people with HIV viral suppression

As with treatment-naïve people, a three-medicine combination is generally recommended when people with HIV who are virally-supressed need to switch to a different ART. People with no resistance mutations can likely switch to any combination that the evidence has found to be highly effective in treatment-naïve people.⁶

However, the use of multiple medicines is associated with additional safety concerns, including polypharmacy, cumulative drug exposure and toxicities.⁹

Two-medicine combinations have been proposed and developed to address these concerns in HIV management.⁹ There is growing evidence that they can maintain viral suppression in people who have been on a three-medicine combination.⁶

Dolutegravir + rilpivirine FDC is considered a reasonable option for people with HIV viral suppression when the use of NRTIs is not desirable.⁸

Efficacy and safety of dolutegravir 50 mg taken concomitantly with rilpivirine 25 mg was demonstrated in two Phase 3, open-label trials.^1,9

Participants (N = 1024; combined total) with viral suppression for 6 months or longer and no history of virologic failure were randomised to stay on their three-medicine combination (current ART) or switch to dolutegravir taken with rilpivirine.⁹

In the pooled analysis of the intention-to-treat population, 95% of participants in each group had viral loads below 50 copies per mL at 48 weeks (primary efficacy endpoint), with an adjusted treatment difference of −0.2% (95% confidence interval [CI] −3.0 to 2.5). Dolutegravir taken with rilpivirine was non-inferior to current ART, with a predefined non-inferiority margin of –8%.⁹

Dolutegravir taken with rilpivirine was also non-inferior to current ART in participants with virological failure during the trial (adjusted treatment difference −0.5%, 95% CI −1.4 to 0.5), with a predefined non-inferiority margin of 4%.⁹ 

Dolutegravir + rilpivirine FDC should not be given to people who have evidence of resistance to either medicine, or people with chronic hepatitis B virus (HBV) infection, because a two-medicine combination may not have adequate anti-HBV activity.⁶

Dolutegravir has been associated with an increased risk of neural tube defects in infants. Dolutegravir-based combinations are not recommended for women who are:⁶

• pregnant and within 12 weeks post-conception
  
• of childbearing potential, sexually active, and not using effective contraception
  
• contemplating pregnancy.
  

Co-administration of dolutegravir + rilpivirine FDC with proton pump inhibitors (PPIs) is contraindicated. PPIs may significantly decrease rilpivirine plasma concentrations, resulting in loss of therapeutic effect.³

Dolutegravir + rilpivirine FDC has been associated with insomnia, headache, depression and suicidal ideation (rarely, and usually in people with pre-existing psychiatric conditions).⁶

Hepatotoxicity, QT interval prolongation, hypersensitivity reactions (including rash and rare cases of Stevens–Johnson syndrome), constitutional symptoms and organ dysfunction (including liver injury) have also been reported.⁶

Dolutegravir + rilpivirine FDC can be used by people with renal insufficiency (creatinine clearance < 30 mL/min), but close monitoring for adverse effects is recommended.⁶

Switching from one effective ART combination to another may be considered when there is a need to:^6-8

• simplify treatment combinations to reduce pill burden and/or dosing frequency, eliminate food or fluid requirements or improve adherence
  
• enhance tolerability and/or decrease short- or long-term toxicity
  
• prevent or mitigate drug–drug interactions
  
• optimise use of ART during pregnancy, when pregnancy is planned or when pregnancy may occur
  
• reduce risks associated with ageing and/or comorbidity, for example, cardiovascular disease risk and diabetes
  
• reduce costs for the few people in Australia who pay full price for their ART medicines.
  

People living with HIV can be cared for using a team-based interdisciplinary ‘shared care’ approach that includes GPs, specialists, nurses, allied health professionals and specialist support services.¹⁰

More information about the shared care approach, including a flowchart, information about training and education, and other tools and resources can be found at ASHM Shared Care for GPs.¹⁰