Bictegravir fixed-dose combination for HIV (Biktarvy)

• The first antiretroviral fixed-dose combination (FDC) containing bictegravir
  Bictegravir is an integrase strand transfer inhibitor with activity against HIV-1 and HIV-2.
• Bictegravir FDC is PBS-listed as an Authority Required (Streamlined) listing
  Guidelines recommend bictegravir FDC as one of the initial regimens for most adults with HIV.
• Resistance has not been detected in treatment-naive trial participants
  Bictegravir FDC has an in-vitro resistance that is improved or equivalent to other integrase strand transfer inhibitors.
• Safety and efficacy for pregnant women remain uncertain
  There are no adequate and well-controlled clinical studies on the use of bictegravir FDC or its component medicines by pregnant women.

Authority Required (Streamlined)

On 1 March 2019, bictegravir + emtricitabine + tenofovir alafenamide fixed-dose combination (FDC), under the brand name Biktarvy, was listed on the PBS as an Authority Required (Streamlined) listing.¹ The medicine will be referred to as bictegravir FDC in this article.

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended that bictegravir FDC be listed under the Section 100 – Highly Specialised Drugs Program (Community Access) for people with HIV infection who meet the following criteria:^2,3

• Initial treatment: Patients must be antiretroviral (ARV) treatment-naive.
• Continuing treatment: Patients must have previously received PBS-subsidised therapy for HIV infection.

Bictegravir FDC is an oral tablet that contains three ARV medicines:⁴

• bictegravir 50 mg
• emtricitabine 200 mg
• tenofovir alafenamide 25 mg.

Bictegravir is an unboosted integrase strand transfer inhibitor (INSTI) with specific activity against HIV-1 and HIV-2.^4,5

It binds to the HIV integrase active site and prevents HIV replication by blocking retroviral DNA strand transfer into host DNA.⁴

Compared with other INSTIs, bictegravir has an in-vitro resistance profile against nine INSTI-resistant site-directed HIV-1 mutants that is similar to dolutegravir and markedly better than raltegravir and elvitegravir.⁵

Emtricitabine and tenofovir alafenamide are nucleoside reverse transcriptase inhibitors.³

Active phosphorylated metabolites of nucleoside reverse transcriptase inhibitors inhibit viral reverse transcriptase and viral DNA synthesis, preventing HIV replication.⁶

Emtricitabine and tenofovir alafenamide are incorporated into viral DNA by HIV reverse transcriptase, leading to DNA chain-termination.⁴

HIV treatment is an active therapeutic and research area. Guidelines and recommendations require regular updates to reflect the availability of new medicines and medicine combinations, and new data from clinical trials.^7-9

Comparative information on HIV ART medicines can be found in the US Department of Health and Human Services (DHHS) Guidelines for the use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and in the European Clinical AIDS Society (EACS) Guidelines.^7,8

Information is also available on the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) website, including Australian-specific commentary on the US DHHS guidelines.⁹

This commentary is updated after every major revision to the DHHS guidelines, and more frequently if required.⁹

These organisations and resources should be referred to for complete and up-to-date information on management for people living with HIV, but some key points have been included below.

PBAC consideration

The PBAC considered bictegravir FDC to be as effective and safe as:^3,10

• tenofovir disoproxil fumarate + emtricitabine + elvitegravir + cobicistat FDC (Stribild) or
  tenofovir disoproxil fumarate + 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.

HLA-B*5701 testing

Testing for the HLA-B*5701 gene variation is not required before prescribing bictegravir FDC.^8,9

In contrast, HLA-B*5701 screening is recommended before starting medicines that contain abacavir, to reduce the risk of potentially life-threatening hypersensitivity reactions.⁸

Patients testing positive for HLA-B*5701 should not receive abacavir.⁸

Renal function

Bictegravir FDC contains tenofovir alafenamide, not tenofovir disoproxil fumarate.⁴

Medicines that contain tenofovir disoproxil fumarate should be avoided for patients with renal disease (creatinine clearance [CrCl] < 60 mL/min).⁹

Tenofovir disoproxil fumarate has been associated with new onset or worsening renal impairment. In addition, adverse renal outcomes are more likely when tenofovir disoproxil fumarate and emtricitabine are coadministered with pharmacokinetic boosters like cobicistat.⁸

Declines in kidney function are less common with tenofovir alafenamide than tenofovir disoproxil fumarate, and tenofovir alafenamide may be used for patients whose CrCl > 30 mL/min.^8,9

Although bictegravir FDC is not recommended for patients with an estimated CrCl < 30 mL/min, dose adjustments are not required in adult patients with an estimated CrCl ≥ 30 mL/min.^4,9

Initiating ART for treatment-naive patients with HIV

For ART-naive patients with HIV, the US DHHS and EACS guidelines recommend an initial regimen of two nucleoside reverse transcriptase inhibitors in combination with a third ART.^7,8

The choice of the third medicine is guided by the regimen’s efficacy, barrier to resistance, adverse effects profile, convenience, comorbidities, concomitant medicines and the potential for drug–drug interactions.⁸

In the October 2018 update of the US DHHS guidelines, bictegravir FDC was classified as one of the recommended initial regimens for most people with HIV (strong recommendation, level I evidence).⁸

Bictegravir FDC was added as an initial option based on data from randomised phase 3 clinical trials that demonstrated its similar efficacy, safety and tolerability to other regimens recommended for most people with HIV (namely, dolutegravir + abacavir + lamivudine and dolutegravir with tenofovir alafenamide + emtricitabine).⁸

Switching ART regimens for patients with HIV viral suppression

Most people living with HIV can achieve and maintain HIV viral suppression with currently available ART medicines, particularly if they have undetectable viral load without side effects.^7,8

However, switching from one effective ART combination to another may be considered when there is a need to:^7-9

• 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.

The fundamental principle of switching is to maintain viral suppression without jeopardising future treatment options.⁸

As with treatment-naive patients, a three-medicine combination is generally recommended when switching patients with viral suppression to a new regimen. Patients with no resistance mutations can likely switch to any regimen that has been shown to be highly effective for treatment-naive patients.⁸

Common adverse events experienced with bictegravir FDC include diarrhoea, nausea, headache and fatigue.^4,8

Other safety issues have been outlined below, but refer to the US DHHS guidelines, EACS Guidelines and ASHM website for further information.

Pregnancy

There are no adequate and well-controlled clinical studies on the use of bictegravir FDC or its component medicines by pregnant women.⁴

The INSTI dolutegravir has been associated with an increased risk of neural tube defects in infants born to women receiving the medicine at the time of conception.^4,8

It is currently unknown whether neural tube defects are a class effect associated with the INSTIs. However, because bictegravir is structurally similar to dolutegravir, a management approach similar to that recommended for dolutegravir should be taken before considering bictegravir-containing ART.^4,8

Dolutegravir is not recommended for women who are:⁸

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

An FDC containing dolutegravir + rilpivirine (Juluca) was listed on the PBS in December 2018. Read a RADAR article about Juluca’s PBS listing.

Advantages and disadvantages

Compared with other INSTIs, bictegravir has the shortest post-marketing experience. The bictegravir component of bictegravir FDC has the following known advantages and disadvantages when used as initial ART for treatment-naive patients with HIV.^7,8

Advantages

• Bictegravir resistance has not been detected in trials with treatment-naive participants.
• Bictegravir bioavailability is not significantly affected by food, so it can be taken without food.
• Bictegravir can be considered for patients who have experienced cardiovascular adverse events with ritonavir- or cobicistat-boosted protease inhibitors, efavirenz, or elvitegravir + cobicistat.

Disadvantages

• Bictegravir oral absorption can be reduced by simultaneous administration with drugs or supplements containing polyvalent cations (for example, Al-, Ca-, or Mg-containing antacids or supplements, or multivitamin tablets with minerals).
• Bictegravir is a CYP3A and UGT1A1 substrate (but not a CYP3A4 inducer or inhibitor) with potential for drug interactions. Interactions between INSTIs and other drugs can be found in Table 19d of the US DHHS guidelines.
• Bictegravir inhibits tubular secretion of creatinine without affecting glomerular function.
• Bictegravir is not recommended with rifamycin-containing medicines for patients with comorbid tuberculosis.

Shared care for people with HIV

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.¹¹

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.¹¹