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

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 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.

HIV TREATMENT CAN NORMALIZE SURVIVAL 3

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

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

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 77% 1 2 TDF/FTC+EVG/c (GS 104-111) 90%, n=867 2 TAF/FTC+EVG/c (GS 104-111) 92%, n=866 3 ABC/3TC+DTG (FLAMINGO) 90%, n=79 3 TDF/FTC+DTG (FLAMINGO) 90%, n=163 4 TDF/FTC+RAL bid (SPRING-2) 85%, n=247 4 ABC/3TC+RAL bid (SPRING-2) 87%, n=164 4 ABC/3TC+DTG (SPRING-2) 86%, n=169 4 TDF/FTC+DTG (SPRING-2) 89%, n=242 5 ABC/3TC+DTG (SINGLE) 88%, n=414 6 TDF/FTC+EVG/c (GS 103) 90%, n=353 TDF/FTC+EVG/c (GS 102) 7 88%, n=348 8 TDF/FTC+RAL bid (QDMRK) 89%, n=386 TDF/FTC+RAL bid (STARTMRK) 9 86%, n=280 0 10 20 30 40 50 60 70 80 90 100 Patients with plasma HIV-1 RNA <50 copies/mL at week 48 (%) 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

2016: THE CHALLENGES OF TODAY Maximise Minimise efficacy toxicity Minimising Maximise toxicity efficacy The Challenges Minimise Minimise Minimise development drug Minimise drug development of of resistance interactions interactions resistance Adapted from Günthard et al. JAMA 2014;312:410 – 25

CASE DISCUSSIONS

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/mm 3 • UECs / LFTs / Lipid profile within normal range VCT , voluntary Counselling and Testing; UECs , Urea, Electrolytes and Creatinine; LTFs, Liver Function Tests

NOMSA’S STORY “I have done a lot of research on HIV, “I have been seen a including local and couple of times at the international hospital outpatient and guidelines. Please treated for minor keep me informed on ailments. I was never any new asked to test for HIV.” developments in the field” “My job is quite involving – I would like “I would like to be medication that is involved in all simple and has fewer decisions concerning side effects. Which is my health ” the best available treatment for me?”

WHICH KEY ATTRIBUTE IS MOST IMPORTANT TO YOU WHEN CHOOSING A REGIMEN FOR NOMSA? 1. Efficacy regardless of viral load 2. High barrier to resistance Vote now! 3. Single-pill regimen 4. No food or time of day restrictions 5. Low potential for DDIs 6. Generally well tolerated 49yr, single mum CD4 1; Viral load 498 955 Legal Secretary. Frequent travel Requests simple, highly efficacious regimen with minimal side effects

WHAT TREATMENT WOULD YOU RECOMMEND? 1.TDF/FTC/Efavirenz 2.TDF/FTC/Nevirapine Vote now! 3.TDF/FTC/Atazanavir/r 4.TDF/FTC/Dolutegravir 5.ABC/3TC/Dolutegravir 6.Other 49yr, single mum CD4 1; Viral load 498 955 Legal Secretary. Frequent travel Requests simple, highly efficacious regimen with minimal side effects

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

DO YOU AGREE WITH HER DOCTOR’S DECISION TO START TB TREATMENT? 1. Yes Vote now! 2. No 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

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

Delay in hospital readmission after receiving culture result due to contact problems On readmission still well but complained of swollen leg Doppler / Ultrasound suggestive of cellulitis and no DVT Develops rapidly progressive epidermolysis

WHAT DO YOU THINK IS A POSSIBLE DIAGNOSIS? 1. Staphylococcus aureus cellulitis 2. Necrotisinig fasciitis (Group A Streptococcus) 3. Cutaneous tuberculosis with TB-IRIS Vote now! 4. Something else

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

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

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

ASIDE FROM COUNSELLING, WOULD YOU CONSIDER: 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 Vote now!

SIMULATION STUDY OF PHARMACOKINETICS WHEN SWITCHING FROM EFV TO DTG 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 4 Mean EFV DTG C 𝜐 * EFV MEC (1 µg/mL) DTG MEC (0.3 µg/mL) 3 concentration (µg/mL) DTG and EFV 2 1 0 0 5 10 15 20 25 30 Post-switch time (days) PK simulation data suggests no dose adjustment of DTG is needed when switching from an EFV-based regimen. Adapted from Generaux G, et al. IWCP 2014. Poster P_36 * mean and 5th-95th percentile ; MEC, minimal effective concentration

Q & A ZAF/TRIM/0005/16a Oct 2016

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