1. 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

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

3. 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

4. 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

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

6. Dose Optimization
Efavirenz

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

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

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

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

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

12. 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

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

14. 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

15. Atazanavir/ritonavir
Dose Optimization
Atazanavir/ritonavir

16. 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

17. Lancet HIV 2016; 3: e343–50

18. 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

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

20. 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

21. 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

22. 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

23. 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

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

25. Key Funders and Supporters
NRCT

26. 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.

27. and
Chulalongkorn University
Thank You