Optimizing Antiretorviral Therapy for Long-Term HIV Care Kiat Ruxrungtham Professor of Medicine Chula Vaccine Research Center (ChulaVRC), Chulalongkorn University; and HIV-NAT, Thai Red Cross AIDS Research Center

Resource Rich vs Limited Settings What ART to start ? Resource Rich vs Limited Settings

What to start the U.S. DHHS, and EACS guidelines 2016 Third ARV NtRTI or NRTI NRTI Cytidine Analog Dolutegravir Evitegravir/cobi1 Raltegravir Darunavir/r TDF ABC* FTC 3TC** + + + + TAF (in FDC with EVG/cobi) Let me summarize the principles in choosing a combined ART regimen in a treatment naïve patient: Choose one from each of these 3 boxes: Box 1: AZT or d4T, or TDF Box 2: 3TC or ddI Box 3: NNRTI-EFV (preferred in most developed countries), or LPV/r, or others. Atazanavir with a once daily option and low/no lipid disorder and 2 pills a day, may be more preferable in the practice when PI-based therapy is the treatment choice. However, longer term data needed. *if HLA B*5701 is negative, for DTG regimen only **only with ABC/DTG EACS 2016 also include RPV 1eGFR>70; 2when VL<100,000 c/ml U.S. DHHS Guidelines April 2015; EACS 2015, BHIVA 2015

What to start in Resource-limited settings? Three drug combination in Naïve Patients 2 Nucleoside RT Inhibitors + NNRTI or Boosted PIs Third ARV NtRTI or NRTI NRTI Cytidine Analog + + EFV* RPV* TDF ABC AZT FTC 3TC + + Let me summarize the principles in choosing a combined ART regimen in a treatment naïve patient: Choose one from each of these 3 boxes: Box 1: AZT or d4T, or TDF Box 2: 3TC or ddI Box 3: NNRTI-EFV (preferred in most developed countries), or LPV/r, or others. Atazanavir with a once daily option and low/no lipid disorder and 2 pills a day, may be more preferable in the practice when PI-based therapy is the treatment choice. However, longer term data needed. Alternative ATV/r* LPV/r WHO guidelines 2013 *Thai Guidelines 2017: EFV 400, RPV for CD4>350, and ATV/r 200/100 for patients on bPIs with VL<50

Does dosage matter? Can we lower the dose to minimize cost and toxicities ? Candidate ARVs for Dose Optimization Trials: Efavirenz, Lopinavir, Atazanavir

Dose Optimization Efavirenz

Standard doses of Efavirenz associated with a higher exposure in Thais/Asians van der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009

DMP-006 trial: EFV Phase II (1996-97) 16 weeks data Hill et al. The Open Infectious Dis J 2010, 4, 85-91

ENCORE1 study Lancet 2014; 383: 1474–82 Conducted by Kirby Institute, Sydney, Asutralia

ENCORE Study: 48 Weeks EFV 400 mg was non-inferior to EFV 600 mg Encore study group. Lancet 2014; 383: 1474–82

ENCORTE1 : 96 weeks results Non-inferiority findings = confirmed The Lancet Infectious Diseases 2015

ENCORTE1 : 96 weeks results on AEs EFV-related AEs (%) Stopping due to EFV-related AEs % % P =0.03 P =0.03 The Lancet Infectious Diseases 2015

Clinical Infectious Diseases® 2015;60(7):1026–32 www.aps.org ENCORE CSF study team Conclusions: With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV replication

Efavirenz 400 – STR ? TDF/FTC + EFV 400 600 mg EFV may be needed for STR with EFV 400 mg TDF/FTC + EFV 400 Atripla The Lancet Infectious Diseases 2015 600 mg EFV may be needed for 1. Pregnancy 2. Tuberculosis - with Rifmapicin

Atazanavir/ritonavir Dose Optimization Atazanavir/ritonavir

Non-inferiority tiral ATV 300 vs 200 boosted with rtv 100 Standard dose of Atazanavir (ATV) was associated with a high exposure in Asians LASA study Non-inferiority tiral ATV 300 vs 200 boosted with rtv 100 van der Lugt J, and Avinhingsanon A. Asian Biomedicine Feb 2009

Lancet HIV 2016; 3: e343–50

LASA Study: Design and Endpoints Atazanavir/r 200 /100 mg OD Primary endpoint proportion of patients whose HIV-RNA <200 c/mL after 48 weeks of treatment Non-inferiority if the lower limit of the 95% CI for the difference in proportion with VF was above -10% in an ITT analysis at 48 weeks N=560 Randomized 1:1 With 2 NRTIs Atazanavir/r 300 /100 mg OD Adults age >18 Yr On boosted PI regimens for  3 mo Plasma HIV-RNA <50 c/ml for 12 mo Assessments: 0, 12, 24, 36, and 48 weeks blinded bilirubin results Stratification by sites, and use of tenofovir, indinavir Type analyses: intention to treat (ITT), per protocol (PP), snap shot (non-completer=failure) analysis PI: protease inhibitor, r: ritonavir, OD: once daily

LASA Study Results at Week 48 N=560 with viral suppressed 3 months ATV/r 200 ATV/r 300 % Patients with HIV-RNA <50 c/ml % Patients Discontinuation P =0.03 P =0.01 P =0.06

Implementation of research findings into the health care system   Next step ! Efficacy study PK study and pilot study Guidelines implementation Randomized control trial with adequate sample size “LASA study” Non-inferiority design, N=560

Cost Saving When Using Lower Dose Atazanavir (from 300 to 200 mg) 5 year savings Up to 1000 million Baht To treat 5000 cases with a 10 % increase/year 30 tab/bottle 60 tab/bottle

EFV 400, especially for those cannot tolerate EFV 600 RPV for CD4>350, and ATV/r 200/100 for patients on bPIs with VL<50

ARV Dose Optimization and Global Cost Saving First-line : EFV 400 mg Will save ~200 million USD to treat 12 million patients /year Second-line : ATV/r 200/50 + DTG Will save 500 million USD to treat 3 million patients /year Andrew Hill. Curr Opin HIV AIDS 2013, 8:34–40

Improve Long-term Outcomes Improve Tolerability By Dose Optimization Efavirenz Lopinavir/r Atazanavir Improve Long-term Outcomes

Key Funders and Supporters NRCT

For the LASA and ENCORE-1 studies We are very grateful to all the study participants; and all of the HIV-NAT, TRC-ARC staffs, the IRBs, DSMBs, and collaborators.

and Chulalongkorn University Thank You