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HIV Medicine From Guidelines to Practice Kiat Ruxrungtham Professor of Medicine, Chulalongkorn University; and HIV-NAT, Thai Red Cross AIDS Research Center Kiat Ruxrungtham Professor of Medicine, Chulalongkorn University; and HIV-NAT, Thai Red Cross AIDS Research Center

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Three Decades of HIV/AIDS Learning and the Future Mid 1990 1981 2012 - 2014 One/ two ARVs Improve survival One/ two ARVs Improve survival 2020 Three ARVs (HAART) Durable undetectable VL Three ARVs (HAART) Durable undetectable VL Earlier HAART non-AIDS death Transmission New TB Earlier HAART non-AIDS death Transmission New TB New strategies Long-acting ARV ? Cure ? New strategies Long-acting ARV ? Cure ? late 1980 Few ARVs More toxicity Few ARVs More toxicity More class ARVs More potent PIs But high pill burden More class ARVs More potent PIs But high pill burden More new ARVs More tolerable More OD options More FDC options Single tablet regimens More new ARVs More tolerable More OD options More FDC options Single tablet regimens Monthly ARV? Cure ? Monthly ARV? Cure ? Evidences and developments Availability and treatment options

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MSM 10-30% MSM 10-30% HIV/AIDS in Thailand

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Rapid Progressors Typical Progressors 15 yrs Normal, Stable CD4+ T cell count Viral load

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CD4 cell count Years After HIV Infection Clinical outcomes No AIDS-complication + No non-AIDS-complication Clinical outcomes No AIDS-complication + No non-AIDS-complication 500 350 200 ? CIPRA HT001 START trial

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Current Update on HIV Treatment 2014

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When to start ART by guidelines GuidelinesCD4Note U.S. DHHS 2014All When the patient is ready and committed to treatment WHO 2013

What to start in Resource-rich settings? NtRTI or NRTI NtRTI or NRTI NRTI Cytidine Analog NRTI Cytidine Analog NNRTI or bPI or Integrase inh. NNRTI or bPI or Integrase inh. ++ TDF ABC* AZT TDF ABC* AZT FTC 3TC FTC 3TC Three drug combination in Nave Patients 2 Nucleoside RT Inhibitors + NNRTI or Boosted PI or Integrase inhibitor Efavirenz Atazanavir/r Darunaivr/r Raltegravir Dolutegravir Evitegravir/cobi 1 Rilpivirine 2 Efavirenz Atazanavir/r Darunaivr/r Raltegravir Dolutegravir Evitegravir/cobi 1 Rilpivirine 2 1 eGFR>70; 2 when VL

How to detect failure and DR? Time-course of HAART Failure Clinical Started HAART 1 234 5 Non- Adherence Non- Adherence Viral load Resistance CD4 drop Time (months years) Thai NHSO guidelines: VL q 6 mo, until VL350, q 1 yr Thai NHSO guidelines: VL q 6 mo, until VL350, q 1 yr

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Viral Load and CD4 Tests

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Virologic Failure The inability to achieve or maintain suppression of viral replication SettingDHHS 2009DHHS 2011WHO 2009 Incomplete suppression after 24 weeks >400*>200*>5000** Virologic Rebound >50>200***>5000 *High Baseline VL (>100,000 c/ml) may take longer than low BL VL **Values of >5 000 copies/ml are associated with clinical progression and a decline in the CD4 cell count ***>200 is associated with evidence of viral evolution and drug-resistance mutation accumulation

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Second-line ART controlled studies StudyNcomparatorsSitesSponsorsEnd point analysis HIV-STAR200 TDF/3TC +LPV/r LPV/r mono Thailand 10 sites HIVNAT, NHSO, Swiss cohort Nov 2011 SECOND- LINE 550 2NRTI +LPV/r RAL +LPV/r All continents 18 countries Kirby Insitute, Australia Sept 2012 ALISA 386 TDF/FTC +LPV/r TDF/3TC +ATV/r Africa SA, Tanzania French NIH May 2013 2LADY 450 TDF/FTC +LPV/r ABC/ddI +LPV/r TDF/FTC +DRV/r Africa Burkina Faso, Cammaroon, Senegal ANRS12169 Sep 2013 EARNEST 1277 2NRTIs +LPV/r RAL +LPV/r LPV/r mono Africa 5 countries MRC, EDCTP Dec 2013 www.clinicaltrials.gov (assessed 22 Apr 2012)

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HIV-STAR Results (HIVNAT, TRC-ARC, Thailand initiated trial) Patients with baseline GSS 2 had a better % with VL< 50 c/ml at 48 weeks of treatment Bunupuradah T, et al,. Antiviral therapy 2012 Jul 2. doi: 10.3851

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SECOND-LINE results

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SECOND-LINE Study RAL/LPV/r NRTIs/LPV/r N= 270 N= 271 83% 81% % patients with VL

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Options after First-line Failure NRTI in the failing regimen NRTI optionThird ARV option TDF failure Guided by resistance test results, or Consider : AZT/3TC Preferred : Lopinavir/ritonavir (LPV/r)* Alternative: Atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r) AZT or ABC failure Guided by resistance test results, or Consider :TDF/FTC or TDF/3TC

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boosted PI : WARNING Serious Drug Interaction 1.Ergotism: ergotamine 2.Rhadomyolysis: statins (simvastatin, etc.) Alternatives: pravastatin, fluvastatin and fibrate derivatives 3.Excessive sedation: benzodiazeoines (diazepam, alprazolam, midazolam,..)except lorazepam 4.Hypotension: Ca-blockers (amlodipine, nifedipine, felopdipine), beta-blockers 5.Cushing syndrome, adrenal insufficiency: with fluticasone 6.Torsades de Pointes (prolong QT and ventricular arrhythmia): cisapride, pimozide; ditiazem; antiarrhythmic flecanide, amiodarone, quinidine etc. 1.Ergotism: ergotamine 2.Rhadomyolysis: statins (simvastatin, etc.) Alternatives: pravastatin, fluvastatin and fibrate derivatives 3.Excessive sedation: benzodiazeoines (diazepam, alprazolam, midazolam,..)except lorazepam 4.Hypotension: Ca-blockers (amlodipine, nifedipine, felopdipine), beta-blockers 5.Cushing syndrome, adrenal insufficiency: with fluticasone 6.Torsades de Pointes (prolong QT and ventricular arrhythmia): cisapride, pimozide; ditiazem; antiarrhythmic flecanide, amiodarone, quinidine etc.

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Ergotism and bPI is not common in patients who were well VL control and on bPIs Thai report N=23 All had VL 250 20 hospitalization (4-20 days) 3 gangrene 2 Amputation 1death Thai report N=23 All had VL 250 20 hospitalization (4-20 days) 3 gangrene 2 Amputation 1death Avihingsanond A. et al in submission 2012 a HCW casewas prescribed bPI as a PEP regimen bPI Ergotamine AEs

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Standard doses of boosted protease inhibitors (bPIs) associated with a high exposure in Asian van der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009

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Cost Saving When Using a Lower Dose Atazanavir : from 300 to 200 mg 5 year savings = 6900 million Baht to treat 5000 cases with a 5% cases increased/yr 5 year savings = 6900 million Baht to treat 5000 cases with a 5% cases increased/yr

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ATV/r: atazanavor/ritonavir, PI: protease inhibitor, HAART: highly active antiretroviral therapy, OD: once daily, TDF: tenofovir Complete enrollment: Dec 2013, expected results by Jan 2015

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Life Expectancy approaches normal in a High-income country after HAART The Netherlands N = 17,580 person-year Median CD4 = 480 (24 wks of Dx) Life expectancy from 25 yo Men = 52.7 years Women =57.8 years The Netherlands N = 17,580 person-year Median CD4 = 480 (24 wks of Dx) Life expectancy from 25 yo Men = 52.7 years Women =57.8 years

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Date of download: 8/25/2012 Copyright The American College of Physicians. All rights reserved. From: Life Expectancy of Persons Receiving Combination Antiretroviral Therapy in Low-Income Countries: A Cohort Analysis From Uganda Ann Intern Med. 2011;155(4):209-216. doi:10.1059/0003-4819-155-4-201108160-00358 Uganda (N=22,315) Life expectancy at 30 yo CD4 150 = 40 years Uganda (N=22,315) Life expectancy at 30 yo CD4 150 = 40 years The life expectancy can be near normal with antiretroviral therapy, especially when ART was initiated at CD4>150 cells

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Thailand: Age and gender distribution HIV/AIDS statistic, BOE, MOPH (data up to Nov 2011) Aging Future Trend Male Female

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Reduced bone mineral density Renal dysfunction 30% of HIV+ patients have abnormal kidney function 1 Increased prevalence 63% of HIV+ patients 2 Increased prevalence 63% of HIV+ patients 2 Emerging co-morbidities in HIV Gupta SK et al. Clin Infect Dis 2005;40:15591585.,Brown TT et al. J Clin Endocrinol Metab 2004;89(3):12001206, Clifford DB. Top HIV Med 2008;16(2):9498 Triant VA et al. J Clin Endocrinol Metab 2007;92:25062512, Patel P et al. Ann Intern Med 2008;148:728736 Cardiovascular disease Neurocognitive dysfunction Impairment present in 50% HIV+ patients 3 Cancer Increased risk of non-AIDS- defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal 5 Increased risk of non-AIDS- defining cancers e.g. anal, vaginal, liver, lung, melanoma, leukemia, colorectal and renal 5 75% increase in risk of acute MI 4

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Drug Interactions with First-line ART and Lipid-Lowering Therapy AntiretroviralContraindicatedTitrate Dose No Dose Adjustment RPV [1] Atorvastatin EVG/COBI/TDF/ FTC [1] Lovastatin Simvastatin Atorvastatin Rosuvastatin DTG [2] ATV/RTV [1] Lovastatin Simvastatin Atorvastatin Rosuvastatin Pitavastatin DRV/RTV [1] Lovastatin Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin EFV [1] Atorvastatin Simvastatin Pravastatin Rosuvastatin RAL [1] 1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert]. Kuritzkes D et al. www.clinicaloptions.com

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Drug Interactions With Oral Contraceptive Pills (OCPs) AntiretroviralEffect on OCPDosing Recommendation RPV [1,2] Ethinyl estradiol AUC 14% Norethindrone: no significant change No dose adjustment EVG/COBI TDF/FTC [1,3] Ethinyl estradiol AUC 25% Norgestimate Weigh the risks and benefits of norgestimate and consider alternative contraceptive DTG [4] No clinically relevant interactionNo dose adjustment ATV/RTV [1,2] Ethinyl estradiol AUC Norgestimate OCP should contain 35 mcg ethinyl estradiol DRV/RTV [1,2] Ethinyl estradiol AUC 44% Norethindrone AUC 14% Additional methods of contraception recommended EFV [1,2] No effect on ethinyl estradiol Active metabolites of norgestimate A reliable method of barrier contraception must be used in addition to hormonal contraceptives RAL [1,2] No clinically relevant interactionNo dose adjustment 1. DHHS Adult Guidelines. February 2013. 2. DHHS Perinatal Guidelines. July 2012. 3. TDF/FTC/EVG/COBI [package insert]. 4. Dolutegravir [package insert]. Kuritzkes D et al. www.clinicaloptions.com

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DrugDrug Interactions Acid-Reducing Medications and Newer ARVs ARVAntacids H2-Receptor Antagonists Proton Pump Inhibitors RPV [1] Give antacids at least 2 hrs before or at least 4 hrs after RPV Give H2-receptor antagonists at least 12 hrs before or at least 4 hrs after RPV Contraindicated EVG/COBI TDF/FTC [1] Separate EVG/COBI/ FTC/TDF and antacid administration by > 2 hrs No clinically relevant DTG [2] RAL DTG should be given 2 hrs before or 6 hrs after taking medications containing polyvalent cations No clinically relevant 1. DHHS Adult Guidelines. February 2013. 2. Dolutegravir [package insert]. Kuritzkes D et al. www.clinicaloptions.com

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Cardiologist Lifetime HIV care Requires an integrated multidisciplinary approach Hepatologist Plastic surgeon Nephrologist Neurologist Endocrinologist Nutritionalist Smoking cessation Gynecologist Adpated From Anna Maria Geretti. London HIV physician

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Can we be the AIDS Free Generation?

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Ending AIDS Policy How and When? Petchsri Sirinirund Advisor on HIV/AIDS Policy and Programme Department of Disease Control, Thailand ICAAP 11, 21 Nov 2013, Bangkok

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50% reduction New Infection In 5 Years 50% reduction New Infection In 5 Years End AIDS In 20 years End AIDS In 20 years Ending AIDS Working Definition 1.New infection

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CD4