CELSENTRI (Maraviroc), an effective option for your treatment-experienced patients with CCR5-Tropic virus

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CELSENTRI – CCR5 antagonist which selectively binds to the human chemokine receptor, preventing CCR5-tropic HIV-1 entering cells:

  • CELSENTRI has a unique MOA and no cross-resistance to other ARV classes1
  • CELSENTRI is generally well tolerated2
  • CELSENTRI has comparable rates of discontinuation with Celsentri + OBT vs. placebo + OBT2

Therapy should be initiated by a physician experienced in the management of HIV infection3

Indication and Dosing

What is CELSENTRI?
CELSENTRI is a CCR5 antagonist which selectively binds to the human chemokine receptor, preventing CCR5-tropic HIV-1 entering cells.

 

Indication
CELSENTRI, in combination with other antiretroviral medicinal products, is indicated for treatment-experienced adult patients infected with only CCR5-tropic HIV-1 detectable.

  • Convenient dosing: No food or time-of-day restrictions; no boosting; few significant DDIs; small tablet size. CELSENTRI is to be taken orally.
    It can be taken with or without food. The
    recommended dose of CELSENTRI
    is 150 mg, 300 mg or 600 mg
    twice daily. It is available as film coated tablets
    containing 150mg or 300mg maraviroc.

Clinically Significant Drug-Drug Interactions

Healthcare providers should ensure that appropriate dose adjustment of CELSENTRI is made when CELSENTRI is co-administered with potent cytochrome P450 (CYP) 3A inhibitors and or inducers because concentrations and therapeutic effects of CELSENTRI may be affected.

Dosing Recommendations3-7

Dosing Recommendations
Neither a potent CYP3A inhibitor nor inducer               
Examples of concomitant medications where CELSENTRI (maraviroc) dose is 300mg AM and 300mg PM:

 

NRTIs: all
NNRTISs: nevirapine, rilpivirine
PI: tipranavir/ritonavir
Integrase inhibitors: raltegravir, dolutegravir
Fusion inhibitor: enfuvirtide

AM

300mg

PM

300mg

Potent CYP3A inducer (without a potent CYP3A inhibitor) ­ ­
Examples of concomitant medications where the CELSENTRI (maraviroc) dose is 2x300mg AM and 2x300mg PM:

 

NNRTIs: efavirenz, etravirine
Antibiotic: rifampicin
Anticonvulsants: carbamazepine, phenytoin
Barbiturate: phenobarbital

AM

2 x 300 mg

PM

2 x 300 mg

Potent CYP3A inhibitor (with or without a potent CYP3A inhibitor) ­ ­
Examples of concomitant medications

 

PIs: all, excluding tipranavir/ritonavir

NNRTI: delavirdine

Antifungals: ketoconazole, itraconazole

Antibiotics: clarithromycin, telithromycin

NS3/4A HCV PIs: telaprevir, boceprevir

AM

150mg

PM

150mg

Further information


For further information on potential drug-drug interactions with CELSENTRI, please see the Summary of Product Characteristics - SPC


For additional information on the use of CELSENTRI with other medication, please visit the University of Liverpool HIV Drug Interaction websitea


a ViiV Healthcare has provided funding to the drug-drug interactions website hosted by the University of Liverpool. The site and its content are independently developed, and owned by, the University of Liverpool. ViiV does not endorse or accept liability for this site.

Safety and Tolerability

CELSENTRI is well tolerated with low discontinuation rates

The safety profile of CELSENTRI is based on 1,374 HIV-1 infected patients who have received at least one dose of CELSENTRI during Phase 2b/3 clinical studies. This includes 426 treatment-experienced patients and 360 treatment-naïve patients who received the recommended dose 300 mg twice daily and a further 588 treatment-experienced and treatment-naïve patients who received 300 mg once daily.

Assessment of treatment-related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (for further information, please see MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (for further information, please see MERIT) infected with CCR5-tropic HIV-1.

 

Grade 2-4 Adverse Events at 48 Weeks

MOTIVATE 1 and 2 (at 48 Weeks): Grade 2-4 adverse events (all causality) ≥ 5% in either arm3

MOTIVATE 1 and 2 (at 48 Weeks): Grade 2-4 adverse events (all causality) ≥ 5% in either arm1
­ CELSENTRI 300mg BID* + OBT (n = 426), % Placebo + OBT (n = 209), %
Gastrointestinal disorders:
Diarrhoea
Nausea
 

8
6

 

10
7

Infections and Infestations:
Upper Respiratory Tract Infection
 

5

 

1

Nervous System Disorders:
Headache
 

2

 

6

General Disorders:
Fatigue
Fever
 

4
6

 

6
4

Pooled analysis revealed no new safety signals between 48 weeks and the end of blinded therapy8

Discontinuations at 48 Weeks

 

MOTIVATE 1 and 2 (at 48 Weeks): Most common adverse events (> 8% incidence) reported with CELSENTRI with frequency rates higher than placebo, regardless of causality3

MOTIVATE 1 and 2 (at 48 Weeks): Most common adverse events (> 8% incidence) reported with CELSENTRI with frequency rates higher than placebo, regardless of causality1
­ CELSENTRI 300mg BID* + OBT (n = 426), % Placebo + OBT (n = 209), %
Upper Respiratory Tract Infection 23 13
Cough 14 5
Pyrexia 13 9
Rash 11 5
Dizziness 9 8

Most common adverse events at 48 Weeks

 

MOTIVATE 1 and 2 (at 48 weeks): Percentage of patients who discontinued due to adverse events

 

 

 

MOTIVATE 1 and 2 (at 48 weeks): Percentage of patients who discontinued due to lack of efficacy

 

 

 

 No new safety signals were identified at 240 weeks for CELSENTRI

Safety Endpoints at 240 Weeks

 

MOTIVATE 1 and 2: Incidence of selected safety endpoints from baseline at 240 weeks3

MOTIVATE 1 and 2: Incidence of selected safety endpoints from baseline at 240 weeks1
Endpoint CELSENTRI 300mg BID* + OBT n (%)
Category C Events 78 (8)
Deaths 46 (5)
Hepatic Failure 5 (0.5)
Infections judged to be SAEs 114 (12)
Malignancies 61 (6)
Myocardial Infarction / Cardiac Ischaemia 26 (3)
Rhabdomyolysis 5 (0.5)
Twice Daily

 

No new safety signals for CELSENTRI were identified based on selected safety endpoints at 240 weeks9

During the observational phase, selected safety endpoints were captured and were also retrospectively identified in the double-blind and open-label phases9

 

Allergy Advice

CELSENTRI contains soya lecithin. If a patient is hypersensitive to peanut or soya, the product should not be used.

Tropism

Viral Tropism

The entry of a virus into host cells is facilitated by the interaction of viral surface structures with coreceptors on the host cell surface10


The preference of a HIV strain to a specific type of coreceptor is called tropism10


HIV-1 enters CD4+ T-cells via the CCR5 or CXCR4 coreceptor10


Some strains of HIV-1, termed dual-tropic, can utilise either coreceptor10


Mixed populations of virus can occur in a patient, which is known as mixed tropism11

 

 

Viral Load and Tropism Testing

Tropism testing is used to identify which coreceptor HIV uses to infect CD4+ cells12. Viral loads can be separated into two categories:
undetectable viral load and detectable viral load.

 

Undetectable viral load

Undetectable viral load
Trofile DNA® Proviral DNA genotypic tests
Description A phenotypic assay of viral DNA for patients with undetectable viral loads13 - Available in the United States only Genotypic testing that is suitable for patients with undetectable viral load14
Specimen used 4mL whole blood15 Cell-associated viral DNA from whole blood16
Sequencing Viral DNA isolated from whole blood cells infected with HIV-115,17.  HIV envelopes encoded by the viral DNA are tested in a cell-based viral infectivity assay15,17 PCR amplification of HIV-1 envelope V3 loop.16 Triplicate Sanger DNA sequencing of V3 loop16
Storage Frozen immediately (-20C), do not centrifuge15 N/A
Testing centre Specimen sent to diagnostic company's lab for testing15 Local laboratories can utilise their own in-house methodologies for testing14
Waiting time Approximately 14 days N/A
Interpretation of data N/A N/A
Results Indicates if virus population can use CCR5, CXCR4, or both15,17 Predicts if CXCR4 is detected or not. Therefore, patient's viral tropism to be determined as CCR5 or dual mixed/CXCR414,16

 

Detectable viral load

Detectable viral load
Trofile ESTA® HIV-1 RNA genotypic testing
Description Trofile® with enhanced sensitivity (ESTA) is a commercially available phenotypic viral RNA assay13. For patients with viral loads ≥ 1000 copies/mL13 Genotypic testing suitable for patients with a detectable viral load14
Specimen used Two 5mL whole blood samples, centrifuge immediately18 HIV-1 envelope obtained from viral RNA14
Sequencing Uses complete gp160 coding region of HIV-1 envelope13. Plasma HIV-1 RNA amplified to generate recombinant viruses, which are used to infect indicator cells expressing CD4+ and either CXCR4 or CCR514 Different approaches to genotypic sequencing exist, including:14 Population-based sequencing: Triplicate Sanger sequencing of the V3 loop

Ultradeep sequencing (UDS): Produces large numbers of clonal sequences from one sample
The Quest Diagnostics® tropism test with reflex to UDS utilises both of these approaches19

Storage Frozen for delivery18 N/A
Testing centre Specimen sent to diagnostic company's lab for testing15 Local laboratories can utilise their own in-house methodologies for testing14
Waiting time Approximately 14 days N/A
Interpretation of data N/A Using a predictive algorithm (e.g. Geno2Pheno)14,16
Results Indicates if virus population can use CCR5, CXCR4, or both15,17 Predicts if CXCR4 is detected or not. Therefore, patient's viral tropism to be determined as CCR5 or dual mixed/CXCR414,16

Resistance

Resistance


CELSENTRI is an effective treatment option in combination with other antiretroviral agents and preferably two other fully active agents

  • HIV drug resistance can make choosing a fully active regimen challenging
    - Despite many advances in modern HIV treatment, drug resistance continues to limit treatment options in patients failing therapy20
    - Acquired drug resistance is a result of resistance mutations caused by drug selective pressures in individuals undergoing antiretroviral therapy20 

CELSENTRI’s unique mechanism of action

- CELSENTRI appears to have a high genetic barrier to resistance21
- No signature mutations have been identified with CELSENTRI22
- No cross-resistance with other antiretroviral agents has been reported1
- There is currently no commercially available assay to determine CELSENTRI susceptibility

 

CELSENTRI can form part of a fully active regimen in treatment-experienced patients

  • Approximately 70% of patients taking CELSENTRI in the MOTIVATE studies who had a weighted optimised background therapy algorithm susceptibility score (WOBTSS) ≥ 2 achieved HIV-1RNA <50 copies/ml at week 4823
  • In a small, prospective, independent study, 92% of 28 triple-class experienced patients that received CELSENTRI in combination with raltegravir and etravirine achieved HIV-1 RNA <50 copies/ml at week 4824

 

MOTIVATE studies:
Virological response by treatment arm and g-WOBTSS*25

 

 

 *  g-WOBTSS = genotypic weighted optimised background therapy susceptibility score

** Twice daily

References

  1. Dorr P, Westby M, Dobbs S et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother. 2005;49(11):4721-4732.
  2. Gulick RM, Lalezari J, Goodrich J, et al; for the MOTIVATE Study Teams. Maraviroc for previously treated patients with R5 HIV-1 infection. N Engl J Med. 2008;359(14):1429-1441.
  3. CELSENTRI (maraviroc) Summary of Product Characteristics
  4. SELZENTRY [prescribing information]. Research Triangle Park, NC: ViiV Healthcare group of companies; April 2015.
  5. Edurant [prescribing information]. Raritan, NJ: Tibotec Therapeutics; 2011.
  6. TIVICAY [prescribing information]. Research Triangle Park, NC: ViiV Healthcare group of companies; 2014.
  7. Vourvahis M, Plotka A, Kantaridis C, Fang A, Heera J. The effects of boceprevir and telaprevir on the pharmacokinetics of maraviroc: an open-label, fixed-sequence study in healthy volunteers. J Acquir Immune Defic Syndr. 2014;65(5):564-570.
  8. Hardy WD, Gulick RM, Mayer H, et al. Two-year safety and virologic efficacy of maraviroc in treatmentexperienced patients with CCR5-tropic HIV-1 infection: 96-week combined analysis of MOTIVATE 1 and 2. J Acquir Immune Defic Syndr. 2010;55(5):558-564.
  9. Gulick RM, Fatkenheuer G, Burnside R, et al. Five-year safety evaluation of maraviroc in HIV-1-infected treatment-experienced patients. J Acquir Immune Defic Syndr. 2014;65(1):78-81.
  10. Berger EA, Murphy PM, Farber JM. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu Rev Immunol 1999;17:657-700.
  11. Svicher V, Balestra E, Cento V, Sarmati L, Dori L, Vandenbroucke I, et al. HIV-1 dual/mixed tropic isolates show different genetic and phenotypic characteristics and response to maraviroc in vitro. Antiviral Res 2011;90:42-53.
  12. Svicher V, D’Arrigo R, Alteri C, et al. Performance of genotypic tropism testing in clinical practice using the enhanced sensitivity version of Trofile as reference assay: results from the OSCAR Study Group. New Microbiol 2010;33:195-206.
  13. Monogram Biosciences. Trofile® DNA http://www.monogrambio.com/hiv-tests/tropism/trofile-dna. Accessed September 2015.
  14. Vandekerckhove L, Wensing A, Kaiser R, et al. European guidelines on the clinical management of HIV-1 tropism testing. Lancet Infect Dis 2011;11:394-407.
  15. Quest Diagnostics. Test Center: Trofile® DNA http://www.questdiagnostics.com. Accessed September 2015.
  16. Quest Diagnostics: HIV-1 Coreceptor Tropism, Proviral DNA, http://www.questdiagnostics.com. Accessed September 2015.
  17. Monogram Biosciences. Trofile® DNA: Sample report https://www.monogrambio.com/sites/monogrambio/files/imce/uploads/TrofileDNA_report_new_watermark.pdf. Accessed September 2015.
  18. Quest Diagnostics. Test Center: Trofile™ Co-Receptor Tropism Assay [19995X], http://www.questdiagnostics.com/testcenter. Accessed September 2015.
  19. Quest Diagnostics. Test centre: HIV-1 corecepor tropism with reflex to ultradeep sequencing, http://education.questdiagnostics.com/faq/FAQ86v1. Accessed September 2015.
  20. World Health Organization. The HIV drug resistance report 2012: World Health Organization; 2012.
  21. Westby M, Smith-Burchnell C, Mori J, et al. Reduced maximal inhibition in phenotypic susceptibility assays indicates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. J Virol. 2007;81(5):2359-2371.
  22. Wensing AM, Calvez V, Günthard HF et al. 2014 Update of the Drug Resistance Mutations in HIV-1. Top Antivir Med 2014; 22(3)-642:650.
  23. Schapiro JM, Boucher CA, Kuritzkes DR, et al. Baseline CD4+ T-cell counts and weighted background susceptibility scores strongly predict response to maraviroc regimens in treatment-experienced patients. Antivir Ther 2011;16:395-404.
  24. Nozza S, Galli L, Visco F, et al. Raltegravir, maraviroc, etravirine: an effective protease inhibitor and nucleoside reverse transcriptase inhibitor-sparing regimen for salvage therapy in HIV-infected patients with triple-class experience. AIDS 2010;24:924-8
  25. European AIDS Clinical Society. Guidelines: Version 7.1 November 2014. http://www.eacsociety.org/files/guidelines_english_71_141204.pdf. Accessed January 2015.

UK/DTGP/0048/16 Date of Prep: March 2017