FOR YOUR HIV PATIENTS LIVING WITH MILD TO MODERATE RENAL IMPAIRMENT(eGFR: 30-69 mL/min/1.73m2)

Building on 20 years’ trusted triple therapy experience

TAF/UK/17-10/MI/1040b Date of preparation: January 2018 Links to prescribing information can be found at the foot of this page

Genvoya® is indicated for the treatment of human immunodeficiency virus 1 (HIV 1) infection without any known mutations associated with resistance to the integrase inhibitor class, emtricitabine or tenofovir as follows: in adults and adolescents aged from 12 years and with body weight at least 35 kg; in children aged from 6 years and with body weight at least 25 kg for whom alternative regimens are unsuitable due to toxicities1

Descovy® is indicated in combination with other antiretroviral agents for the treatment of adults and adolescents (aged 12 years and older with body weight at least 35 kg) infected with human immunodeficiency virus type-1 (HIV-1).2

What do the bhiva guidelines state about tdf and renally impaired patients?

BHIVA advises against the continued use of tdf in patients with worsening renal function3

“The nephrotoxic potential of TDF appears to be increased, and the reversibility of eGFR decline following TDF discontinuation diminished, in those with eGFR <90 mL/min/1.73 m2

“We recommend against continued use of TDF and atazanavir in individuals with worsening renal function who have developed or are approaching CKD stages 3–5 if acceptable alternative ARV agents are available (GPP)”

BHIVA AUDIT REQUIREMENTS

  • Number of individuals approaching CKD stages 3–5 (<60mL/min/1.73m2) on ARVs who continue TDF or atazanavir
  • A record of the rationale for keeping these patients on non-recommended regimens in renal impairment

What is the risk of heart disease in your patients with renal impairment?

The expanded QRISK algorithm underlines CKD risk and now includes eGFR <60 mL/MIN/1.73 m2

  • CKD is a risk factor for cardiovascular mortality4
  • QRISK3 now includes CKD stage 3 as a significant risk factor for cardiovascular disease5
  • CKD can effectively double the risk of cardiovascular disease5
* Variables are the same as QRISK 2 but with chronic kidney disease (stage 3, 4, or 5) and additional age interactions for: migraine, corticosteroid use, and systemic lupus erythematosus. † Interaction with age; hazard ratios evaluated at mean age. Adapted from Hippisley-Cox J, et al. 2017.

The risk of death and morbidity is increased as a patient's eGFR falls below 75 mL/min2

  • The presence of proteinuria would suggest an even higher risk of death and mortality when combined with lower eGFRs4

Genvoya® could be an effective choice for your clinically appropriate patients living with renal impairment

Genvoya® contains a targeted version of Tenofovir (taf) which reduces plasma levels by 90% compared to TDF in clinical trials*6–10

Tenofovir alafenamide (TAF) prodrug molecule mode of action

mode of action

The conversion of TAF into TFV occurs primarily in lymphoid cells, minimising systemic exposure and reducing off-target effects

* Tenofovir alafenamide (TAF) in the context of HIV and this presentation is referring to the co formulated combinations outlined above. TAF is NOT licensed for use as a single agent for the treatment of HIV infection.

THE LONG-TERM EFFICACY OF GENVOYA® HAS BEEN STUDIED IN RENALLY IMPAIRED PATIENTS OUT TO 144 WEEKS11

Study 112: Suppressed Adults with Renal Impairment switched to GENVOYA® (Week 144)11

Primary Endpoint

Change from baseline in glomerular filtration rate at Week 24.

Secondary Endpoint

Efficacy, safety, and tolerability observed through Week 144.

Adapted from Podzamczer D, et al. 2017.

baseline characteristics

* Some regimens included >1 third agent; therefore, total percentage >100%. Adapted from Post FA, et al. 2016.

durable efficacy And A long-term safety profile WAS ESTABLISHED OUT TO 144 weeks*

In renally impaired switch patients, Genvoya® achieved high rates of virologic suppression (83%) and was well tolerated through 144 weeks11

Adapted from Podzamczer D, et al. 2017.

Safety Summary

  • Most common AEs: URTI (15%), diarrhoea (13%), and arthralgia (14%)
  • AEs, grades, and frequencies were generally similar in participants with baseline eGFR <50 vs. ≥50 mL/min
  • No participants discontinued study drug for AEs between Weeks 96 and 144

The primary endpoint, no statistically significant change in eGFR at 24 weeks, was met.

Study 112 was a single-arm, open-label study in which 242 virologically suppressed subjects with mild to moderate renal impairment (eGFR 30–69 mL/min/1.73 m2) were switched to Genvoya® and followed prospectively. The primary endpoint was evaluating changes in estimated and actual GFR through Week 24. * HIV <50 copies/mL out to 48, 96 and 144 weeks. † For renally impaired patients switched to Genvoya®. ‡ HIV <50 copies/mL. § HIV ≥50 copies/mL.

Renally impaired patients who switched to GENVOYA® experienced statistically significant Improvements in renal biomarkers

These improvements were statistically significant from baseline and continued out to 144 weeks11

Changes over time in renal biomarkers: RBP:Cr, ß2m:Cr

96 participants had clinically significant albuminuria (UACR ≥3.39 mg/mmol) at baseline which was resolved in 47% through Week 14411

Changes in urinary albumin-creatinine ratio

Adapted from Podzamczer D, et al. 2017.

AND there were no discontinuations due to renal AEs AFTER 96 weeks

5 participants with poorly controlled comorbidities discontinued prior to week 96 for changes in eGFR or worsening of their underlying renal disease11

Safety Summary

  • No cases of proximal renal tubulopathy or Fanconi syndrome through Week 14411
  • AEs, grades, and frequencies were generally similar in participants with baseline eGFR <50 vs. ≥50 mL/min

0 cases of proximal renal tubulopathy have occurred in over 3000 switch and naïve patients at Weeks 48 (n=3015),6,13–1896 (n=2192)15,19,20 and 144 (n=889)15,21 in clinical trials*

Study 112 was a single-arm, open-label study in which 242 virologically suppressed subjects with mild to moderate renal impairment (eGFR 30–69 mL/min/1.73 m2) were switched to Genvoya® and followed prospectively. The primary endpoint was evaluating changes in estimated and actual GFR through Week 24. * Studies included other FTAF-based regimens.

GENVOYA® has A 3-YEAR safety profile for renally impaired patients, including IMPROVEMENTS IN BMD PARAMETERS

Statistically significant improvements in hip and spine BMD from baseline after 144 weeks11

Hip and Spine BMD

* P-values were for change relative to baseline and based on 2-sided Wilcoxon signed-rank test.
  • Both hip and spine BMD increased significantly overall and more markedly for those on preswitchTDF (p<0.001 for both)
  • Spine BMD increased significantly for those without preswitch TDF use (p=0.03)
Adapted from Podzamczer D, et al. 2017. Study 112 was a single-arm, open-label study in which 242 virologically suppressed subjects with mild to moderate renal impairment (eGFR 30–69 mL/min/1.73 m2) were switched to Genvoya® and followed prospectively. The primary endpoint was evaluating changes in estimated and actual GFR through Week 24.

GENVOYA® IS The only INSTI STR with superior efficacy* in both ART-naïve and switch studies†14,21,22

* HIV <50 copies/mL out to 48, 96 and 144 weeks. † In randomised clinical trials which compared Genvoya to alternative regimens. ART-naïve studies 104 and 111 met superiority at week 144 against Stribild. Switch study 109 met superiority at week 48 versus TDF-based regimens.

Descovy®▼; -based triple therapy offers patients switching from TDF-based regimens:

  • Trusted triple therapy – building on 20 years of a successful treatment with triple therapy in real-world settings23,24
  • Targeted tenofovir delivery – innovation bringing you a 90% reduction in plasma levels with Tenofovir Alafenamide (TAF)1,6–10 which provides:
    • Established efficacy* – maintained virological suppression (overall 95% vs. 93%)25 across varied clinical trial populations at Week 48
      • Durable efficacy – sustained to Week 144 (83%§)11
    • A long-term safety profile out to 144 weeks – zero cases of tubulopathy with statistically significant improvements in hip and spine bone mineral density in clinical trials at Weeks 48 (n=2146),13–15,17,18 96 (n=1422)15,17,19 and 144 (n=153)15
* HIV <50 copies/mL out to 48, 96 and 144 weeks. ‡ 1.7% (95% CI: 0.1, 3.4) – pooled data at Week 48. † Difference of any regimen including 2 NRTIs plus a third agent. § For renally impaired patients switched to Genvoya® (please note some patients switched from non-TDF based therapies). ¶ Numbers calculated to reflect the number of patients receiving TAF minus those who discontinued study drug for any reason.

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References and abbreviations

References
  1. SmPC Genvoya®. Available at: https://www.medicines.org.uk/emc/medicine/31225. Accessed January 2018.
  2. SmPC Descovy®. Available at: https://www.medicines.org.uk/emc/medicine/31764. Accessed January 2018.
  3. British HIV Association (BHIVA) guidelines for the treatment of HIV-1-positive adults with antiretroviral therapy 2015 (2016 interim update). Available at: http://www.bhiva.org/documents/Guidelines/Treatment/2016/treatment-guidelines-2016-interim-update.pdf. Accessed January 2018.
  4. Matsushita K, et al. Lancet 2010; 375(9731): 2073–2081.
  5. Hippisley-Cox J, et al. BMJ 2017; 357: j2099.
  6. Sax PE, et al. Lancet 2015; 385(9987): 2606–2615.
  7. Lee WA, et al. Antimicrob Agents Chemother 2005; 49(5): 1898–1906.
  8. Birkus G, et al. Antimicrob Agents Chemother 2007; 51(2): 543–550.
  9. Babusis D, et al. Mol Pharm 2013; 10(2): 459–466.
  10. Gupta SK, et al. IAS 2015. Vancouver, Canada. Oral TUAB0103.
  11. Podzamczer D, et al. IAS 2017; Paris, France. Poster #MOPEB0288.
  12. Post FA, et al. CROI 2016; Boston, MA, USA. #680.
  13. Gallant J, et al. Lancet HIV 2016; 3(4): e158–e165.
  14. Mills A, et al. Lancet Infect Dis 2016; 16(1): 43–52.
  15. Gilead Sciences. Data on File UK-HIV-17-03.
  16. Gaur AH, et al. CROI 2016; Boston, MA, USA. Poster 817.
  17. Orkin C, et al. Lancet HIV 2017; 4(5): e195–e204.
  18. DeJesus E, et al. Lancet HIV 2017; 4(5): e205–e213.
  19. Raffi F, et al. HIV Glasgow 2016. Glasgow UK. Presentation O125.12. Wohl D, et al. J Acquir Immune Defic Syndr 2016; 72: 58–64.
  20. Wohl D, et al. J Acquir Immune Defic Syndr 2016; 75(2): 58–64.
  21. Arribas JR, et al. J Acquir Immune Defic Syndr 2017; 75: 211–218.
  22. Pozniak A, et al. J Acquir Immune Defic Syndr 2016; 71: 530–537.
  23. European AIDS Clinical Society (EACS) guidelines. Version 9.0. October 2017. Available at: http://www.eacsociety.org/files/guidelines_9.0-english.pdf. [accessed: January 2018]
  24. Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Updated October 2017. Available at: http://aidsinfo.nih.gov/guidelines. [accessed January 2018].
  25. Rockstroh J, et al. IAS 2017; Paris, France. Poster #MOPEB0289.
Abbreviations: 3TC, lamivudine; ABC, abacavir; AE, adverse event; ART, antiretroviral therapy; ARV, antiretroviral; ß2m, beta-2 microglobulin; BHIVA, British HIV Association; BL, baseline; BMD, bone mineral density; CCR5, C–C chemokine receptor type 5; CG, Cockcroft–Gault; CI, confidence interval; CKD, chronic kidney disease; Cr, creatinine; CrCl, creatinine clearance; D:A:D, data collection on adverse events of anti-HIV drugs; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; GPP, good practice point; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; OD, once daily; OR, odds ratio; PI, protease inhibitor; Q, quartile; RBP, retinol-binding protein; RNA, ribonucleic acid; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir; UACR, urine albumin:creatinine ratio; UPCR, urine protein:creatinine ratio; URTI, upper respiratory tract infection.