THE EVOLUTION OF 1 ST LINE THERAPY Piotr Budnik November 2016 - - PowerPoint PPT Presentation

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THE EVOLUTION OF 1 ST LINE THERAPY Piotr Budnik November 2016 ZAF/TRIM/0005/16a Oct 2016 This event is sponsored by GSK in the interest of advancing the scientific and educational knowledge of healthcare professionals. GSK does not approve

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THE EVOLUTION OF 1ST LINE THERAPY

Piotr Budnik November 2016

ZAF/TRIM/0005/16a Oct 2016

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This event is sponsored by GSK in the interest of advancing the scientific and educational knowledge of healthcare professionals. GSK does not approve or recommend the use of medicines in any way other than is in the approved package

inserts. For full prescribing

information refer to the package insert.

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HIV TREATMENT CAN NORMALIZE SURVIVAL

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VIIV/TRIM/0028/14i(1) - May 2015

THE EVOLUTION OF HIV THERAPY

FDA. Antiretroviral drugs used in the treatment of HIV infection http://www.fda.gov/ForPatients/Illness/HIVAIDS/Treatment/ucm118915.htm Accessed August 2015

FDA news release November 2015 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm471300.htm Accessed November 2015

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VIIV/TRIM/0028/14i(1) - May 2015

1995–2003: HAART HELPED DRIVE ADVANCEMENTS IN HIV THERAPY

Meta-analysis shows that from 1995 to 2010 the overall mean efficacy of initial therapy for HIV-1 improved

Lee et al. PLoS One 2014;9:e97482

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VIIV/TRIM/0028/14i(1) - May 2015

MEAN EFFICACY OF INITIAL REGIMEN CONTINUES TO RISE FROM 77%1 (2005–2010) TO TODAY’S 48W RESULTS

10 20 30 40 50 60 70 80 90 100 TDF/FTC+RAL bid (STARTMRK) TDF/FTC+RAL bid (QDMRK) TDF/FTC+EVG/c (GS 102) TDF/FTC+EVG/c (GS 103) ABC/3TC+DTG (SINGLE) TDF/FTC+DTG (SPRING-2) ABC/3TC+DTG (SPRING-2) ABC/3TC+RAL bid (SPRING-2) TDF/FTC+RAL bid (SPRING-2) TDF/FTC+DTG (FLAMINGO) ABC/3TC+DTG (FLAMINGO) TAF/FTC+EVG/c (GS 104-111) TDF/FTC+EVG/c (GS 104-111) Patients with plasma HIV-1 RNA <50 copies/mL at week 48 (%)

2 2 3 3 4 4 4 4 5 6 7 8 9 3TC = lamivudine; ABC = abacavir; DTG = dolutegravir; EVG/c = elvitegravir/cobicistat; FTC = emtricitabine; RAL = raltegravir; TAF = tenofovir alafenamide fumarate; TDF = tenofovir disoproxil fumarate

1. Lee et al. PLoS ONE 2014;9:e97482; 2. Wohl et al. abstract 113LB presented at CROI 2015; 3. Clotet et al. Lancet 2014;383:2222–31; 4. Raffi et al. Lancet 2013;381:735–43; 5.

Walmsley et al. N Engl J Med 2013;369:1807–18; 6. DeJesus et al. Lancet 2012;379:2429–38; 7. Sax et al. Lancet 2012; 379: 2439–48; 8. Eron Jr et al. Lancet Infect Dis 2011;11:907– 15; 9. Lennox et al. Lancet 2009;374:796–806

86%, n=280 89%, n=386 90%, n=353 88%, n=348 88%, n=414 89%, n=242 86%, n=169 90%, n=867 92%, n=866 90%, n=79 90%, n=163 85%, n=247 87%, n=164 77%1

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2016: THE CHALLENGES OF TODAY

Adapted from Günthard et al. JAMA 2014;312:410–25

Minimising toxicity Minimise drug interactions Maximise efficacy Minimise development

f resistance

Maximise efficacy Minimise development of resistance Minimise drug interactions Minimise toxicity

The Challenges

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CASE DISCUSSIONS

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VCT , voluntary Counselling and Testing; UECs , Urea, Electrolytes and Creatinine; LTFs, Liver Function Tests

Nomsa: Clinical presentation

49 year old. Single mum.
Secretary at busy legal practice. Works full
time. Travels frequently
Doesn’t drink or smoke.
Diagnosed in March 2014 at a VCT centre

(self-referral).

Presented with oral thrush. Otherwise in

good general condition

HIV-1 RNA 498,955 c/mL
CD4 1 cell/mm3
UECs / LFTs / Lipid profile within normal

range

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NOMSA’S STORY

“My job is quite involving – I would like medication that is simple and has fewer side effects. Which is the best available treatment for me?” “I would like to be involved in all decisions concerning my health ” “I have done a lot of research on HIV, including local and international

guidelines. Please

keep me informed on any new developments in the field” “I have been seen a couple of times at the hospital outpatient and treated for minor

ailments. I was never

asked to test for HIV.”

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1. Efficacy regardless of viral load
2. High barrier to resistance
3. Single-pill regimen
4. No food or time of day restrictions
5. Low potential for DDIs
6. Generally well tolerated

WHICH KEY ATTRIBUTE IS MOST IMPORTANT TO YOU WHEN CHOOSING A REGIMEN FOR NOMSA?

Vote now!

49yr, single mum CD4 1; Viral load 498 955 Legal Secretary. Frequent travel Requests simple, highly efficacious regimen with minimal side effects

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1.TDF/FTC/Efavirenz 2.TDF/FTC/Nevirapine 3.TDF/FTC/Atazanavir/r 4.TDF/FTC/Dolutegravir 5.ABC/3TC/Dolutegravir 6.Other

WHAT TREATMENT WOULD YOU RECOMMEND?

Vote now!

49yr, single mum CD4 1; Viral load 498 955 Legal Secretary. Frequent travel Requests simple, highly efficacious regimen with minimal side effects

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LET’S CONTINUE

Nomsa: Clinical presentation

Started on TDF/FTC/EFV
Returns after 2 weeks with a non productive

cough and occasional fever. No dyspnoea.

Induced sputum negative for Tuberculosis
But given her symptoms and chest

radiograph findings, her doctor starts her on treatment for tuberculosis

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1. Yes
2. No

DO YOU AGREE WITH HER DOCTOR’S DECISION TO START TB TREATMENT?

Vote now!

49yr, single mum CD4 3; Viral load 358 754 Legal Secretary. Frequent travel Requests simple, highly efficacious regimen with minimal side effects Cough, Fever and abnormal chest radiograph

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Returns 1 month later

Reports back pain and swollen feet
CXR unchanged, WCC 12, CRP 104,

PCT normal

VL <40 CD4 186
Not unwell, diagnosed with cellulitis of

her left leg

Admitted for intravenous Ertapenem

and improves

On the day of discharge she has a

temperature spike and a culture was taken

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Delay in hospital readmission after receiving culture result due to contact problems On readmission still well but complained

f swollen leg

Doppler / Ultrasound suggestive of cellulitis and no DVT Develops rapidly progressive epidermolysis

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1. Staphylococcus aureus cellulitis
2. Necrotisinig fasciitis (Group A Streptococcus)
3. Cutaneous tuberculosis with TB-IRIS
4. Something else

WHAT DO YOU THINK IS A POSSIBLE DIAGNOSIS?

Vote now!

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Cryptococcal antigen 1:2560 Meropenem and Linezolid Liposomal Amphotericin B and Fluconazole CSF: negative for cryptococcus, normal LP results Progressive pulmonary infiltrates with ICU ventilation

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Extensive recurrent debridement Tissue Culture positive for cryptococcus neoformans Complicated hospital stay TB treatment discontinued

TISSUE CULTURE

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After prolonged ICU stay Nomsa has a lot of stressors . She hasn’t been able to return to work and her finances are very troubling Struggling with depression and has lost her will to live, she feels alone and desperate No one to look after her teenage daughter, and she doesn’t feel like getting out of bed most days and isn't sure if she takes her pills every night

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1. Prescribing an antidepressant only
2. Interrupting antiretroviral therapy
3. Decreasing her dose of Efavirenz to 400mg daily
4. Changing her Efavirenz to Dolutegravir
5. Change her treatment to ABC/3TC/DTG

ASIDE FROM COUNSELLING, WOULD YOU CONSIDER:

Vote now!

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SIMULATION STUDY OF PHARMACOKINETICS WHEN SWITCHING FROM EFV TO DTG

Adapted from Generaux G, et al. IWCP 2014. Poster P_36 *mean and 5th-95th percentile; MEC, minimal effective concentration

Post-switch time (days) 5 10 15 20 25 30 4 3 2 1 DTG and EFV concentration (µg/mL) Mean EFV EFV MEC (1 µg/mL) DTG C𝜐

DTG MEC (0.3 µg/mL)

PK simulation data suggests no dose adjustment of DTG is needed when switching from an EFV-based regimen.

Upon discontinuation of 600 mg EFV QD and starting 50 mg DTG QD, there is no time frame post switch where both DTG and EFV mean plasma concentrations fall below their respective minimal effective concentrations

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Q & A

ZAF/TRIM/0005/16a Oct 2016

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Adverse Events should be reported to GlaxoSmithKline via telephone to +27 11 745 6000 or via e-mail to aereporting.sna@gsk.com