1. HIV Cases “What to Start” Dr Anton Pozniak Chelsea and Westminster Hospital London

2. Case-SP A 57 year old caucasian man presented to the emergency department with progressive difficulty in swallowing over the last 4 weeks. He is hypertensive and has diet controlled diabetes and asthma and takes inhaled B2 agonists and inhaled steroids He had seen his family practitioner who saw oral thrush and thought it was related to his diabetes/ inhalers and gave him amphotericin lozenges He had been diagnosed with HIV a year before but had not attended any clinics as he “felt well”

3. Case-SP He had extensive oral thrush and had severe dysphagia BP 145/90 mmHg He was admitted and treated with fluconazole Social History –Lives alone is MSM –Smokes 15 a day –Alcohol 20 units a week, no recreational drugs Drugs –Salbutamol inhaler –Fluticasone Inhaler –Amlodopine –St Johns Wort for depression

4. Case-SP Labs STD screen negative FBC,U and Es, LFTs Normal, Cr CL 69 mls/min, Urine protein +no glucose CD4 33 cells/uL VL 365000 copies/ml Hep B immune Hep C negative STS negative Resistance test and HLA B5701 awaited Framingham 10 year risk risk 18%

5. You decide to start ARVs RegimenDHHS [1] IAS [2] EACS [3] EFV/TDF/FTCPreferredRecommended ATV/RTV + TDF/FTCPreferredRecommended DRV/RTV + TDF/FTCPreferredRecommended RAL + TDF/FTCPreferredRecommended LPV/RTV + TDF/FTCAlternative Recommended EFV + ABC/3TCAlternative Recommended ATV/RTV + ABC/3TCAlternative Recommended DRV/RTV + ABC/3TCAlternative Recommended NVP + TDF /FTCAcceptableAlternativeRecommended MVC + TDF/FTCAcceptableAlternative RPV + TDF /FTCAlternativeNo recommendation RAL + ABC/3TCAlternativeNo recommendation 1. DHHS Guidelines, March 2012. 2. T. JAMA. 2012;304:321-333. 3. EACS Guidelines, November 2011.

6. You decide to start ARVs What is your choice of main agent? NNRTI PI/r Integrase other

7. Difficulties in choosing-which 3 rd agent? NNRTI- –may have transmitted dug resistance –RPV may not be effective in High viral load Integrase –BD –and may have NRTI transmitted dug resistance PI/r – drug interactions, – diabetes, lipids

8. NNRTI/NRTI and Prevalence of Transmitted Drug Resistance Eacs 2011 SPREAD

9. If you decide to give a boosted PI Drug Interactions What Drugs have significant interactions with a boosted PI? 1 St Johns Wort 2 Fluticasone 3 Amlodopine 4 None 5 all

10. What NRTI back bone? AZT/3TC ABC/3TC TDF/FTC DDI/3TC OTHER

11. Difficulties in choice of NRTI AZT- –lipodystrophy –BD ABC –High Viral load –Cardiovascular risk(smoker and diabetic and BP) TDF – Renal changes, – Bone changes

12. CVD – Do drugs matter? D:A:D: Recent and/or cumulative ARV exposure and risk of MI Adapted from Lundgren JD, et al. CROI 2009. Oral presentation 44LB. RR of cumulative exposure/year 95%CI # PYFU: 138,109 74,407 29,676 95,320 152,009 53,300 39,157 # MI: 523 331 148405 554 221 139 RR of recent* exposure yes/no 95%CI 1.9 1.5 1.2 1.0 0.8 0.6 ZDVddIddCd4T3TCABCTDF # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 # MI: 298 197 150 221 228 221 IDVNFVLPV/RTVSQVNVPEFV PI † NNRTI 1.2 1.13 1.0 1.1 0.9 1.9 1.5 1.2 1.0 0.8 0.6 *Current or within past 6 months; † Approximate test for heterogeneity: p=0.02; **not shown due to low number of patients receiving ddC RR of cumulative exposure/year 95%CI NRTI CVD=cardiovascular disease; ARV=antiretroviral; MI=myocardial infarction; RR=relative risk; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor; PYFU=patient years of follow up **

13. 0.27 0.21 0.51 1.16 -0.26 -0.43 -0.45 -0.53 0.008 -0.11 0.03 0.31 -0.8 -0.4 0 0.40.81.2 Mantel-Haenszel Risk Difference % (95% CI) All Trials n=26 GSK Trials n=16 NIH Trials n=5 Academic Trials n=5 Created from Ding X, et al. CROI 2011. Poster presentation 808. Meta-analysis of Phase II–IV RCTs including ABC –Mean follow up 1.6 person-years per subject –Patients: 80% male (mean age=39 years) Limitations –Young adults, so underlying MI risk low –Other CV risk factors usually unknown –Unvalidated MIs –Some studies had a PI control group CVD: Do drugs matter? FDA meta-analysis of abacavir and MI CVD=cardiovascular disease; FDA=Food and Drug Administration; MI=myocardial infarction; RCTs=randomised controlled trials; CV=cardiovascular; PI=protease inhibitor

14. Chronic renal disease: ART risk factors 6,843 patients (5,136 male), median age 43 yrs, 90.1% exposed to cART, CD4 450 cells/mm 3, 21.7% hypertension, 4.9% diabetes Median follow up 3.7 years 2-fold increased risk if hepatitis C RNA+ Adapted from Mocroft A, et al. AIDS. 2010;24:1667–8. Multivariate analysis IRR/ year p Tenofovir1.16<0.0001 Indinavir1.12<0.0001 Atazanavir1.210.0003 Lopinavir/r1.080.030 % progressed to CKD Incidence: 1.05 (0.91–1.18)/100 PYFU Months ART=antiretroviral therapy; PYFU=patient years follow up; IRR=incidence rate ratio

15. 1. Adapted from McComsey G, et al. JID. 2011;203:1791–801. ACTG 5224 & SMART: BMD loss with ART initiation ~2-4% at 1-2 yrs 1 Low bone density/fracture: Relationship to ART ART=antiretroviral therapy; BMD=bone mineral density; DC=drug conservation; VS=viral suppression; NRTI=nucleoside reverse transcriptase inhibitor; NNRTI=nonnucleoside reverse transcriptase inhibitor; PI=protease inhibitor; DXA=dual-energy X-ray absorptiometry

16. Case-SP Resistance was wild type He starts EFV TDF FTC

17. Case AP 35 year old Asian women presents with Night sweats, weight loss and cough CXR - RUL cavity and infiltrates AAFB - smear positive and started on RZHE Had an HIV test and was positive CD4 was 35 cells/uL

18. Case AP As her CD4 was<50 cells/uL she was offered ARVs within 2 weeks of starting and tolerating her TB meds What ARV combination would you offer her? What is your choice of main agent? NNRTI-Efavirenz PI/r-Lopinavir/r Integrase-Raltegravir other

19. Case AP Started Efavirenz but couldn't tolerate it What would you offer her? NNRTI-Nevirapine PI/r-Lopinavir/r Integrase-Raltegravir other

20. Case AP What would you offer her? NNRTI-Nevirapine-less efficacy ? Drug interaction PI/r-Lopinavir/r major interaction with rifampicin so switch to rifabutin or double dose lopinavir/r or high dose ritonavir 400mg bd Integrase-Raltegravir 400 or 800mg bd Other-4 nucleosides