ARIA Study Shows Superior Efficacy of Triumeq(R) for Treatment-naive Women Living with HIV

PR65130

LONDON, England and DURBAN, South Africa, July 18, 2016 /PRNewswire=KYODO JBN/ --

     ViiV Healthcare today presented 48-week data from the phase IIIb,

open-label, international, multi-centre ARIA study which showed superior

efficacy for Triumeq(R) (dolutegravir/abacavir/lamivudine) compared with

atazanavir boosted with ritonavir (ATV/r) plus tenofovir disoproxil

fumarate/emtricitabine (TDF/FTC) in 495 treatment-naive women living with

HIV.[1] Results show statistically superior viral suppression (HIV-1 RNA ＜50

c/mL) rates at week 48: 82% versus 71% (adjusted difference 10.5%, 95% CI:

3.1%-17.8%, p=0.005) respectively.[1] ARIA was a non-inferiority study with a

pre-specified analysis for superiority. Both non-inferiority and superiority

endpoints were met, with superiority being driven by lower rates of both

virological failures and discontinuations due to adverse events (AEs) in the

dolutegravir/abacavir/lamivudine group.[1]

(Logo: http://photos.prnewswire.com/prnh/20160223/336449LOGO )

    "Women account for over half of the almost 35 million adults living with

HIV worldwide,  yet unfortunately they are consistently under-represented in

HIV clinical trials," said John C Pottage, Jr, MD, Chief Scientific and Medical

Officer, ViiV Healthcare. "For this reason, we are committed to ensuring that

the specific treatment needs of women are investigated. This trial not only

provides physicians with important additional information about Triumeq, it

also builds on the strong body of evidence supporting the efficacy of

dolutegravir-based regimens in a broad range of patient populations."

    The safety profile of dolutegravir/abacavir/lamivudine was favourable

compared to ATV/r plus TDF/FTC, with fewer drug-related AEs reported on the

dolutegravir/abacavir/lamivudine arm (33% vs 49%); there were also fewer AEs

leading to discontinuation compared to those in the ATV/r plus TDF/FTC arm (4%

vs 7%).[1]

    Drug-related AEs reported in the dolutegravir/abacavir/lamivudine arm

included, nausea (31 individuals / 13%), diarrhoea (12 / 5%), headache (5 / 2%)

and dyspepsia (4 / 2%).[1] In the ATV/r plus TDF/FTC group, drug-related AEs

included nausea (35 / 14%), diarrhoea (18 / 7%), ocular icterus (18 / 7%),

dyspepsia (15 / 6%), headache (14 / 6%) and jaundice (13 / 5%).[1]

    There were fewer subjects meeting virologic non-response criteria (VL

＞50c/mL) in the dolutegravir/abacavir/lamivudine arm (6%) compared to the other

group (14%) at week 48.[1] Of the women that met protocol-defined virologic

withdrawal criteria, none on the dolutegravir/abacavir/lamivudine arm had

treatment-emergent resistance mutations to the components of

dolutegravir/abacavir/lamivudine, compared with one in the comparator group. [1]

    About HIV

    HIV stands for the Human Immunodeficiency Virus. Unlike some other viruses,

the human body cannot get rid of HIV, so once someone has HIV they have it for

life. There is no cure for HIV, but effective treatment can control the virus

so that people with HIV can enjoy healthy and productive lives.[2]

    About HIV in women

    Globally, HIV/AIDS is the leading cause of death for women of reproductive

age (15-44 years old)[3] and infection rates in young women (aged 15-24) are

twice as high as those seen in young men.[4] Despite the scale of the

challenge, women are routinely under-represented in HIV clinical trials.[5]

This may be in part due to lack of child-care services, exclusions from study

protocols due to the potential for pregnancy and lack of support in the

home.[5] As a result there are gaps in our knowledge about issues regarding

antiretroviral treatments that are particular to women.[5]

    ARIA study design

    ARIA is a phase IIIb randomised, open-label, international, multi-centre

study designed to demonstrate the non-inferior antiviral activity of fixed-dose

dolutegravir/abacavir/lamivudine (Triumeq) compared with atazanavir boosted

with ritonavir (ATV/r) plus tenofovir disoproxil fumarate/emtricitabine

(TDF/FTC) in treatment-naive adult women over 48 weeks.[6] While ARIA is a

non-inferiority study, there was a pre-specified analysis for superiority. ARIA

also evaluated the safety and tolerability of dolutegravir/abacavir/lamivudine

compared to ATV/r plus TDF/FTC arm.[6] 495 treatment-naive adult women were

enrolled in the study.[6]

    About Triumeq(R)

    Triumeq is a once-daily dolutegravir-based regimen, containing the

un-boosted integrase strand transfer inhibitor (INSTI) dolutegravir and the

nucleoside reverse transcriptase inhibitors (NRTIs) abacavir and lamivudine.

    Two essential steps in the HIV life cycle are replication - when the virus

turns its RNA copy into DNA - and integration - the moment when viral DNA

becomes part of the host cell's DNA. These processes require two enzymes called

reverse transcriptase and integrase. NRTIs and INSTIs interfere with the action

of the two enzymes to prevent the virus from replicating. This decrease in

replication will lead to less virus being available to cause subsequent

infection of uninfected cells.

    The latest data for Triumeq, including the ARIA data presented at IAC

2016,[1] build on existing clinical trial data demonstrating that

dolutegravir-based regimens are efficacious and generally well-tolerated in a

broad range of people living with HIV (PLHIV) , including treatment-naive,

treatment-experienced and those who have developed resistance to multiple HIV

drugs.[7],[8],[9],[10],[11]

    Triumeq is a registered trademark of the ViiV Healthcare group of companies.

    Important Safety Information (ISI) for Triumeq(R) (abacavir, dolutegravir,

and lamivudine) tablets[12]

    Note: this is taken from the US label and local variations apply. Please

refer to applicable local labelling.

    FDA Indications and Usage: Triumeq is indicated for the treatment of human

immunodeficiency virus type 1 (HIV-1) infection.

    Limitations of Use:

    Triumeq alone is not recommended in patients with:

    - Current or past history of resistance to any components of Triumeq

    - Resistance-associated integrase substitutions or clinically suspected

INSTI resistance because the dose of dolutegravir in Triumeq is insufficient in

these subpopulations. See full prescribing information for dolutegravir

    BOXED WARNING: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE

HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B VIRUS (HBV):

    Hypersensitivity Reactions:

    - Serious and sometimes fatal hypersensitivity reactions have occurred with

abacavir-containing products

     - Hypersensitivity to abacavir is a multi-organ clinical syndrome

     - Patients who carry the HLA-B*5701 allele are at a higher risk of

experiencing a hypersensitivity reaction to abacavir; although,

hypersensitivity reactions have occurred in patients who do not carry the

HLA-B*5701 allele

     - Triumeq is contraindicated in patients with a prior hypersensitivity

reaction to abacavir and in HLA-B*5701-positive patients. All patients should

be screened for the HLA-B*5701 allele prior to initiating therapy or

reinitiation of therapy with Triumeq, unless patients have a previously

documented HLA-B*5701 allele assessment

     - Discontinue Triumeq as soon as hypersensitivity reaction is suspected.

Regardless of HLA-B*5701 status, permanently discontinue Triumeq if

hypersensitivity cannot be ruled out, even when other diagnoses are possible

     - Following a hypersensitivity reaction to Triumeq, NEVER restart Triumeq

or any other abacavir-containing product

    Lactic Acidosis and Severe Hepatomegaly with Steatosis:

    - Lactic acidosis and severe hepatomegaly with steatosis, including fatal

cases, have been reported with the use of nucleoside analogues

    Exacerbations of Hepatitis B:

    - Severe acute exacerbations of HBV have been reported in patients who are

co-infected with HBV and HIV-1 and have discontinued lamivudine, a component of

Triumeq. Monitor hepatic function closely in these patients and, if

appropriate, initiate anti-hepatitis B treatment

    CONTRAINDICATIONS

    Triumeq is contraindicated in patients:

     - who have the HLA-B*5701 allele

     - with prior hypersensitivity reaction to abacavir, dolutegravir, or

lamivudine

     - receiving dofetilide (antiarrhythmic)

     - with moderate or severe hepatic impairment

    WARNINGS AND PRECAUTIONS

    Hypersensitivity Reactions to Dolutegravir:

      - Hypersensitivity reactions have been reported and were characterized by

rash, constitutional findings, and sometimes organ dysfunction, including liver

injury. The events were reported in ＜1% of subjects receiving TIVICAY(R) in

Phase 3 clinical trials

     - Clinically, it is not possible to determine whether a hypersensitivity

reaction with Triumeq would be caused by abacavir or dolutegravir. Discontinue

Triumeq and other suspect agents immediately if signs or symptoms of

hypersensitivity reaction develop

    Effects on Serum Liver Biochemistries in Patients with Hepatitis B or C

Co-infection:

    - Patients with underlying hepatitis B or C may be at increased risk for

worsening or development of transaminase elevations with use of Triumeq. In

some cases the elevations in transaminases were consistent with immune

reconstitution syndrome or hepatitis B reactivation, particularly in the

setting where anti-hepatitis therapy was withdrawn

     - Appropriate laboratory testing prior to initiating therapy and

monitoring for hepatotoxicity during therapy with Triumeq are recommended in

patients with underlying hepatic disease such as hepatitis B or C

    Use With Interferon- and Ribavirin-based Regimens: Hepatic decompensation,

some fatal, has occurred in HIV-1/hepatitis C virus (HCV) co-infected patients

receiving combination antiretroviral therapy and interferon alfa with or

without ribavirin. Patients receiving interferon alfa with or without ribavirin

and Triumeq should be closely monitored.

    Immune Reconstitution Syndrome: including the occurrence of autoimmune

disorders with variable time to onset, has been reported.

    Fat Redistribution or accumulation has been observed in patients receiving

antiretroviral therapy.

    Myocardial Infarction (MI):

    - An observational study showed an increase in MI with abacavir; a

sponsor-conducted, pooled analysis did not show increased risk. In totality,

the available data are inconclusive

     - The underlying risk of coronary heart disease should be considered when

prescribing antiretroviral therapies, including abacavir, and action taken to

minimize all modifiable risk factors (eg, hypertension, hyperlipidemia,

diabetes mellitus, smoking)

    Use With Certain Antiretroviral Products: Triumeq should not be

administered concomitantly with other products containing abacavir or

lamivudine.

    ADVERSE REACTIONS: The most commonly reported (greater than or equal to2%)

adverse reactions of at least moderate intensity in treatment-naive adults

receiving Triumeq were insomnia (3%), headache (2%), and fatigue (2%).

    DRUG INTERACTIONS

    - Co-administration of Triumeq with certain inducers of UGT1A and/or CYP3A

may reduce plasma concentrations of dolutegravir. Consult the full Prescribing

Information for Triumeq for more information

     - Administer Triumeq 2 hours before or 6 hours after taking polyvalent

cation-containing antacids or laxatives, sucralfate, oral supplements

containing iron or calcium, or buffered medications. Alternatively, Triumeq and

supplements containing calcium or iron can be taken with food

    USE IN SPECIFIC POPULATIONS

    - Pregnancy Category C: Triumeq should be used during pregnancy only if the

potential benefit justifies the potential risk. An Antiretroviral Pregnancy

Registry has been established

     - Nursing Mothers: Breastfeeding is not recommended due to the potential

for HIV transmission and the potential for adverse reactions in nursing infants

     - Patients with Impaired Renal Function: Triumeq is not recommended in

patients with creatinine clearance ＜50 mL/min

     - Patients with Impaired Hepatic Function: If a dose reduction of

abacavir, a component of Triumeq, is required for patients with mild hepatic

impairment, then the individual components should be used

    Full US Prescribing Information for Triumeq is available at:

https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Triumeq/pdf/TRIUMEQ-PI-MG.PDF

    About ViiV Healthcare

    ViiV Healthcare is a global specialist HIV company established in November

2009 by GlaxoSmithKline (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to

delivering advances in treatment and care for people living with HIV. Shionogi

(TYO: 4507) joined in October 2012. The company's aim is to take a deeper and

broader interest in HIV/AIDS than any company has done before and take a new

approach to deliver effective and new HIV medicines,  as well as support

communities affected by HIV. For more information on the company, its

management, portfolio, pipeline, and commitment, please visit

http://www.viivhealthcare.com

    1. C. Orell et al. Superior efficacy of dolutegravir/abacavir/lamivudine

(DTG/ABC/3TC) fixed dose combination (FDC) compared with ritonavir (RTV)

boosted atazanavir (ATV) plus tenofovir disoproxil fumarate/emtricitabine

(TDF/FTC) in treatment-naive women with HIV-1 infection (ARIA Study). Presented

at the International AIDS Conference (IAC), 18-22 July 2016, Durban, South

Africa. Abstract #10215.

    2. World Health Organization (WHO). 2016. HIV/AIDS media fact sheet.

Available at: http://www.who.int/mediacentre/factsheets/fs360/en  Last accessed

July 2016.

    3. UNAIDS, 2016-2021 Strategy On the Fast-Track to end AIDS. Available at:

http://www.unaids.org/sites/default/files/media_asset/20151027_UNAIDS_PCB37_15_18_EN_rev1.pdf

Last accessed July 2016.

    4. UNAIDS Factsheet - Adolescents, young people and HIV. Available at:

http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/factsheet/2012/20120417_FS_adolescentsyoungpeoplehiv_en.pdf

Last accessed July 2016.

    5. Curno, J. Mirjam et al. A Systematic Review of the Inclusion (or

Exclusion) of Women in HIV Research: From Clinical Studies of Antiretrovirals

and Vaccines to Cure Strategies. Journal of Acquired Immune Deficiency

Syndromes (JAIDS). 2016 Feb 1;71(2) :181-8.

    6. ClinicalTrials.gov (NCT01910402). Available at:

https://clinicaltrials.gov/ct2/show/NCT01910402  Last accessed June 2016.

    7. Raffi F, Jaeger H, Quiros-Roldan E, Albrecht H, Belonosova E, Gatell JM,

Baril J-G, Domingo P, Brennan C, Almond S, Min S, for the SPRING-2 Study Group.

Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive

adults with HIV-1 infection (SPRING-2 study): 96 week results from a

randomised, double-blind, non-inferiority trial. Lancet Infect Dis.

2013;13(11):927-935.

    8. Walmsley S, Baumgarten A, Berenguer J, et al. Brief Report: Dolutegravir

plus abacavir/lamivudine for the treatment of HIV-1 infection in Antiretroviral

therapy-naive patients: Week 96 and Week 144 Results from the SINGLE randomized

clinical trial. Journal of Acquired Immune Deficiency Syndromes (JAIDS).

2015;70(5):515-519.

    9. Molina J, et al. Once-daily dolutegravir versus darunavir plus ritonavir

for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results

from a randomised, open-label, phase 3b study. Lancet HIV. 2015;2:e127-136.

    10. Cahn P, Pozniak AL, Mingrone H, Shuldyakov A, Brites C,

Andrade-Villanueva JF, Richmond G, Buendia CB, Fourie J, Ramgopal M, Hagins D,

Felizarta F, Madruga J, Reuter T, Newman T, Small CB, Lombaard J, Grinsztejn B,

Dorey D, Underwood M, Griffith S, Min S, for the extended SAILING Study Team.

Dolutegravir versus raltegravir in antiretroviral-experienced,

integrase-inhibitor-naive adults with HIV: week 48 results from the randomised,

double-blind, non-inferiority SAILING study. Lancet. 2013;382(9893) :700-708.

    11. Castagna S, et al. Dolutegravir in antiretroviral-experienced patients

with raltegravir- and/or elvitegravir-resistant HIV-1: 24-week results of the

Phase III VIKING-3 study. J Infect Dis. 2014;210:354-62.

    12. Triumeq(R) (dolutegravir/abacavir/lamivudine) US prescribing

information. Available at:

https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Triumeq/pdf/TRIUMEQ-PI-MG.PDF

Source: ViiV Healthcare