APACC 2016 HIV drug resistance. Shinichi Oka, MD, PhD. AIDS Clinical Center (ACC) National Center for Global Health and Medicine (NCGM)

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1 APACC 2016 HIV drug resistance Shinichi Oka, MD, PhD. AIDS Clinical Center (ACC) National Center for Global Health and Medicine (NCGM)

2 HIV drug resistance 1. Current situation of ART and TDR in Japan 2. Current situation of ART and TDR in Vietnam 3. Basic understandings of acquired DRMs 4. How to stop EFV without inducing DRM

3 Changes of NRTIs for initial therapy in the past two decades ABC+3TC TDF+XTC d4t+3tc

4 Use ratio (%) Recent trends of NRTIs usage in May 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% その他の Others 組み合わせ EZC ABC/3TC TVD TDF/FTC year

5 Changes of key drugs for initial therapy in the past two decades NNRTI PI INSTI DTG LPV DRV EFV

6 Use ratio (%) Recent trends of key drugs usage in May 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% year その他 others DTG(TRI) EVG(STB) RAL DRV FPV ATV LPV/r RPV(CMP) ETR EFV

7 (n) CD4 counts in patients on cart in ACC >200/μL: 94.7% >500/μL: 52.2% 2014 CD4 (/μl)

8 (n) HIV-RNA in patients on cart in ACC Most patients are well controlled with current cart 2014 undetectable: 84.7% <200 c/ml: 96.8% *just started cart in 10 cases * HIV-RNA (copies/ml)

9 and Cascade of care at ACC % (?) Problem in Japan Acquired drug resistance is NOT a major issue of ART in Japan ACC data

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11 14% 13% 12% 11% 10% 9% 8% 7% 6% 5% 4% 3% 2% 1% 0% Annual prevalence of TDR HIV in Japan between 2003 and 2012 NRTI NNRTI 12,0% PI All 9,8% 8,7% 7,9% 9,1% 8,2% 5.9% 7,9% 6,9% 5,2%

12 NRTI resistant mutations in newly diagnosed cases

13 NNRTI and PI resistant mutations in newly diagnosed cases

14 Current situation of ART and TDR in Japan 1. A key drug of the first line ART is changing over time. 2. PIs were the most frequently used in this decade. 3. However recently, INSTI has been mainly selected. 4. Current ART have been very effective in terms of viral suppression. Almost all patients on ART achieved VL suppression below 20 copies/ml. 5. Annual prevalence of TDR has been slightly increasing but still below 10% in the past two years.

15 HIV drug resistance 1. Current situation of ART and TDR in Japan 2. Current situation of ART and TDR in Vietnam 3. Basic understandings of acquired DRMs 4. How to stop EFV without inducing DRM

16 Expand of cart and new cases in Vietnam 250,000 cases were reported as of DEC 2011 No of patients on cart Annual new cases

17 Hanoi cohort in National Hospital of Tropical Diseases - HIV-infected patients on ART were enrolled - Background: 1. Number of patients on ART is expanding rapidly 2. ART is implemented based on WHO guidelines 3. CRF01-AE is predominant What to follow; 1. Monitoring of ART 2. Side effects due to ART in Vietnamese

18 True LTFU: patients who stopped visiting the clinics for at least 3 months after their last visit, and did not return by the end of the follow-up period (December 31, 2013). 2015, 10(9): e

19 2016, 11(3): e

20 Consecutive 300 newly diagnosed cases were enrolled each year

21 Current situation of ART and TDR in Vietnam 1. ART is expanding rapidly in this decade. Annual new cases have been decreasing since Patient cohorts revealed very high retention rate and low true LTFU (3.1%) 3. First line ART was very effective. However, there were still ADIs including TB. 4. Prevalence of TDR during was still low (4.2%).

22 HIV drug resistance 1. Current situation of ART and TDR in Japan 2. Current situation of ART and TDR in Vietnam 3. Basic understandings of acquired DRMs 4. How to stop EFV without inducing DRM

23 Patients with < 400 copies/ml (%) Treatment success with NFV+AZT+3TC (ITT) NFV: 10 tablets/day AZT: 4 capsules/day 3TC: 2 tablets/day Total: 16 tablets/day 53% Time after commencement of therapy (weeks) 63% Tsuchiya, Oka et al. J Clin Virol 27: , 2003

24 Proportion of patients without primary mutations Emergence of primary mutation of NFV L90M only 90% D30N only 80% 77% D30N and/or L90M No. at risk Time after commencement of therapy (weeks) No. of cases with censored data No. of cases with mutation D30N only L90M only D30N and/or L90M Tsuchiya, Oka et al. J Clin Virol 27: , 2003

25 Proportion of patients without primary mutations VL at week 12 and emergence of drug resistance A: viral load < 400 copies/ml at week 12 94% B: viral load > 400 copies/ml at week 12 63% P<0.05 No. at risk Time after commencement of therapy (weeks) No. of cases with censored data A B* No. of cases with mutation Tsuchiya, Oka et al. J Clin Virol 27: , 2003

26 Time lag of DRMs emergence in plasma and PBMC Time lag of DRMs emergence in plasma and PBMC, and VL (days) (G73S,L90M) 21(D30N,M46V) 6(L10I) 17(A71V) 17(D30N) 18(L90M) 17(M46L) 22(M36I) 14(D30N) 17(N88D) 1(D30N) 14(M36I) 13(M46I) 12(L10I,A71V,I84V,L90M) R 2 = p < (I54V,A71V,V82A) 21(L10F,A71V) 21(N88D) 14(N88D) 16(I84V) 10(M46I) 18(A71V,I84V) 6(A71T) 5(L90M) 1(N88D) 12(V77I) 13(A71V) 6(V77I) 16(L90M) 5(M46I,I84V) 17(V77I) 20(I54V) 9(A71T) 7(I84V) 2(L10I,L90M) 10(L90M) 20(M36I,V82I) 2(I84V) 16(M36L) 3(I84V) 16(A71T) 15(M46I) 13(L10I) 15(L10I) 20(M46I) 22(A71T) (K20M) Viral load (/ml) Bi, Oka et al. JAIDS 34: 1-6, 2003

27 Prevalence of DRMs in naïve and primary Pts DRMs in pre-treatment patients (PDR) RT region 6/237 PR region 5/ % 2.0 % DRMs in primary infected patients (TDR) RT region 2/ % PR region 2/ % RT or/and PR regions 3/ % Ida, Oka et al. (unpublished data)

28 Time to disappearance of DRMs Time to disappearance of DRMs after cessation of ART (M) P=0.03 n=11 P=0.01 P=0.04 n=14 n=11 P=0.01 n=12 Plasma-RT PBMC-RT Plasma-PR PBMC-PR Bi, Oka et al. AIDS Res Hum Retrovirus 23: 43-50, 2007

29 Basic understandings of acquired DRMs 1. Adherence is the most important factor for ARD. Pill burden, side effects, etc. 2. VL at week 12 after initiation of ART is critical for treatment success 3. ADRMs appear in plasma first and then in PBMC under drug selection pressure 4. ADRMs disappear in plasma first and then in PBMC under no drug selection pressure

30 HIV drug resistance 1. Current situation of ART and TDR in Japan 2. Current situation of ART and TDR in Vietnam 3. Basic understandings of acquired DRMs 4. How to stop EFV without inducing DRM

31 How to stop ART Of course, ART should not be interrupted. However, at the extremely situations such as natural disaster or budget depletion, and if drug supply was stopped ----, When discontinue ART, in general, stop all drugs simultaneously in order to avoid inducing drugresistance.

32 How to stop ART Of course, ART should not be interrupted. However, at the extremely situations such as natural disaster or budget depletion, and if drug supply was stopped ----, When discontinue ART, in general, stop all drugs simultaneously in order to avoid inducing drugresistance except EFV.

33 Efavirenz (EFV) Advantages Disadvantages Single Tablet Regimen (EFV/TDF/FTC) Reasonable price CNS side effects Easy development of resistance Only a single mutation is required to confer high-level NNRTI resistance.

34 EFV-ART with Poor Adherence Viral Load (copies/ml) EFV+TDF/FTC 10 6 K103N

35 EFV Resistance after Interrupting Therapy Viral Load (copies/ml) EFV+AZT+ddI K103N CD4 300 (/mm 3 ) 10 4 liver damage Sep Mar Sep Mar

36 Emergence of K103N after cessation of EFV Viral Load (copies/ml) EFV K103N AZT+ddI functional monotherapy due to longer half-life Do not stop all drugs simultaneously, when stop EFVcontaining regimen Viruses replicating under EFV selective pressure. EFV+AZT+ddI

37 How to avoid inducing EFV resistance When discontinue EFV-based HAART, 1. Stop EFV first before the other drugs 2. Substitute EFV with PI prior to interruption

38 Stopping EFV first before the other agents Viral Load (copies/ml) EFV Ideally, almost simultaneously disappear AZT+ddI EFV+AZT+ddI about 1 weeks AZT+ddI Viruses replicating under no selection pressure.

39 Substitute EFV with PI prior to interruption Viral Load (copies/ml) EFV Viruses begin to replicate under no selection pressure AZT+ddI 10 5 DRV+rtv about 1 weeks 10 2 EFV+AZT+ddI DRV+rtv+AZT+ddI

40 Plasma efavirenz concentration (mm) BBRC 319: , 2004 non-*6 *6 heterozygote *6/*6 CYP2B6 genotype

41 Interruption of EFV in CYP2B6 516TT holders higher conc. EFV 10 6 Viral Load (copies/ml) AZT+ddI extremely longer functional monotherapy K103N Viruses replicating under EFV selective pressure. EFV+AZT+ddI

42 How to stop EFV without inducing DRM 1. EFV is the most widely used ARV in the world. 2. Basically, EFV should not be interrupted. 3. If we have to stop EFV, - Substitute EFV with PI prior to interruption - Stop EFV first around 1 week before the other drugs - pay special attention to slow EFV metabolizers

43 HIV drug resistance 1. Current situation of ART and TDR in Japan 2. Current situation of ART and TDR in Vietnam 3. Basic understandings of acquired DRMs 4. How to stop EFV without inducing DRM