Long-term HIV treatment: The Importance of Initial Antiretroviral Regimen...

Long-term HIV treatment:The Importance of Initial

Antiretroviral Regimen Selection

Contents

Currently, Life-time treatment is needed for PLHIV

Long-term HIV treatment:The Importance of Initial Antiretroviral Regimen Selection

Integrase inhibitor is an optimal choice for HIV naive patients.

HIV reservoirs is a challenge for HIV cure

岳永松等. HIV感染者体内DNA储存库的临床研究进展.中华内科杂志.2017,56(7):529-531

HIV genome is integrated into cellular DNA.

Productively infected CD4+ T cells were continuously eliminated.

Resting CD4+ T cells (memory T cells) act as HIV reservoirs, which could not be recognized by the Immune system.

HIV reservoirs can be found in peripheral blood HIV-infected cells including mononuclear cells and all subpopulations of CD4+ T cells. Lymph nodes and gut-associated lymphoid tissue (GALT) are the major HIV reservoirs. Moreover, central nervous system and other organs can also act as HIV reservoirs.

Katusiime C, Ocama P, Kambugu A.S et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia.PLoS Pathog. 2007 Apr;3(4):e46.

Patients with antiretroviral therapy for 50 weeks still had persistent viremia

(single copy assay) and this is not related with the timing of initiating therapy.

HIV

-1R

NA

(lo

g1

0 拷

贝/m

lLong-term stable inhibition of viral replication is needed

‡

Comorbidities Prevalence in PLWH is Increasing, Regardless of Age

5

US Commercial Claims Database, 2009-2013

Meyer N, et al. ICAAC 2015; San Diego. Oral

Retrospective, observational analysis using Commercial (N=36,298), Medicaid (N=26,246), and Medicare

(N=1,854) claims to evaluate prevalence of comorbid conditions in HIV-infected patients

Contents




Expert opinion: The best regimen should be used as the first line choice.

7

“Our first shot at HIV is our best shot. That is my attitude”

Someone prepares for success, while others prepare for treatment. The one who prepares

for anti-HIV therapy is with soft heart and patience and will keep the best for last while the

one who prepares for success will use heavy bomber to attack HIV. As you may know, this

is what I always mention when tackling infectious diseases. Of course, I would like to take

chance to say it earlier with more active attitudes.

Our first shot at HIV is our best shot. That is my attitude. … I am by nature an optimist and it

is absolutely right in my opinion to say “do the best today and tomorrow there will be better

methods ”to my patients. And it is always true that we found better methods later.

Opinions from Dr. David Ho

1.2017年2月13日GSK北京办公室.GSK感染疾病治疗领域研发部执行/高级副总裁Zhi Hong博士就“如何更好的帮助HIV患者：最佳实践分享”对戴蒙德艾滋病研究中心主任和首席执行官David Ho博士进行访谈. 2 Katusiime C, Ocama P, Kambugu A. Basis of selection of first and second line highly active antiretroviral therapy for HIV/AIDS on genetic barrier to resistance: a literature review. Afr Health Sci. 2014 Sep;14(3):679-81.

Andrew KambuguMakerere University

Use of antiretroviral regimens with a high resistance barrier is a key factor for persistent success.

NRTI:核苷逆转录酶抑制剂； NNRTI: 非核苷逆转录酶抑制剂；PI: 蛋白酶抑制剂；EFV:依非韦伦；NVP:奈韦拉平；RPV: 利匹韦林；ETR:依曲韦林; FTC/3TC:拉米夫定/恩曲他滨；ABC:阿巴卡韦；TDF:替诺福韦；AZT:齐多夫定

WHO HIV drug resistance report 2017

终点

基因

型（

%）

WHO HIV Drug Resistance Report 2017

• Prevalence of acquired HIV drug resistance by drug class and country• The Prevalence of acquired HIV drug resistance of NRTI & NNRTI were

high after treatment failure

Statistically significant increases in the prevalence of NNRTI PDR were observed over time across all LMICregions studied by year of sampling

The prevalence of NNRTI PDR was higher among individualsstarting first-line ART with prior ARV drug exposure, comparedto ARV drug naive individuals in all regions.


Of the 11 countries with PDR survey results, 6 had prevalence of any PDR greater than 10%

10

WHO 2017 HIV drug resistance report

Overall, levels of PDR were driven by NNRTI resistance,10 which exceeded 10% in six of the countries.

2017 WHO guideline recommendation：Regimen with high resistance barrier as 1st line


When the levels of NNRTI PDR have reached or exceeded 10%, transition to a

non-NNRTI-based regimen should be urgently considered

DTG is a INSTI with high resistance barrier, and recommended as first-line

alternative by WHO guideline

With increasing access of DTG in resource limited countries, it should be

preferred to use as first line choice when NNRTI PDR is over 10%

prominent efficacygood virologic/immune response

as the main treatment target.

high barrier to resistance

key matter for successful long-

term treatment 1,2,3

good complianceguarantee of effective antiretroviral

therapy, not satisfactory in Chinese

patients 4,5

favorable safety profile & less AE a requisite for sustained treatment effect 1,6

From the long-term treatment perspective, the optimal

drug for initiating antiretroviral therapy should be with:

1 张美等. 艾滋病长期免费抗病毒治疗疗效和换药原因分析.北京医学,2016,38(12):1286-1289 2 Su Y et al. The prevalence of HIV-1 drug resistance among antiretroviral treatment naïve individuals in mainland China: a meta-analysis.PLoS One. 2014 Oct 24;9(10):e110652. 3 叶晟等. 12 例艾滋病人抗病毒治疗失败情况及耐药分析.中国预防医学.2010,37(12):2342-2343 4 孙丽君等.农村地区艾滋病抗病毒治疗依从性及应对策略分析.中国艾滋病性病.2007,13(4):317-320 5 秦小超等.600例AIDS高效抗反转录病毒治疗临床研究.广西医科大学学报.2013,30(5):722-724 6 刘百义等.门诊艾滋病患者处方点评和药物相互作用分析.中国药房.26(2):153-155

‡

4 Integrase inhibitors

White K, et al . CROI 2018. Boston, MA. Poster 532. 13

Dolutegravir, 2013Bictegravir, 2018

N N

O-

O

Me

HN

O

NH

ON

NO

Me

F

K+

N

O

O

OH

OH

MeO

F

Cl

Raltegravir, 2007 Elvitegravir , 2013

PRT/DLG/0009/15

0 10 20 30 40 50 60 70 80 90 100

TDF/FTC+RAL bid (STARTMRK)

TDF/FTC+RAL bid (QDMRK)

TDF/FTC+EVG/c (GS 102)

TDF/FTC+EVG/c (GS 103)

ABC/3TC+DTG (SINGLE)

TDF/FTC+DTG (SPRING-2)

ABC/3TC+DTG (SPRING-2)

ABC/3TC+RAL bid (SPRING-2)

TDF/FTC+RAL bid (SPRING-2)

TDF/FTC+DTG (FLAMINGO)

ABC/3TC+DTG (FLAMINGO)

TAF/FTC+EVG/c (GS 104-111)

TDF/FTC+EVG/c (GS 104-111)

TAF/FTC/BIC(GS 1489)

TAF/FTC/BIC(GS 1490)

The proportion of participants with HIV-1 RNA <50 c/ml (%) at 48 weeks.

2

2

3

3

4

4

4

4

5

6

7

8

9

1.Lee et al. PLoS ONE 2014;9:e97482;

2.Wohl et al. abstract 113LB presented at CROI 2015; 3.Clotet et al. Lancet 2014;383:2222–31;

4.Raffi et al. Lancet 2013;381:735–43; 5.Walmsley et al. N Engl J Med 2013;369:1807–18;

6.DeJesus et al. Lancet 2012;379:2429–38;7.Sax et al. Lancet 2012; 379: 2439–48;

8.Eron Jr et al. Lancet Infect Dis 2011;11:907–15;9.Lennox et al. Lancet 2009;374:796–806

10. Gallant J, et al. Lancet 2017;390:2063-72.

11.Sax P, et al. Lancet 2017;390:2073-82

86%, n=280

89%, n=386

90%, n=353

88%, n=348

88%, n=414

89%, n=242

86%, n=169

90%, n=867

92%, n=866

90%, n=79

90%, n=163

85%, n=247

87%, n=164

The efficacy of viral suppression has been increased

by INIs from 77%1 (2005-2010年) to >85%

77%1

92%, n=314

89%, n=320

10

11

PRT/DLG/0009/15

48 WEEK VIROLOGICAL RESULT OF

PHASE 3 CLINICAL DEVELOPMENT PROGRAM

DTG BIC EVG RAL

Naïve

patients

SINGLE study(n=833)1:

DTG/3TC/ABC superior to

EFV/FTC/TDF

1489 study(n=600)6:

B/F/TAF non-inferior to

DTG/3TC/ABC

104 and 111 study(n=1733)10:

E/C/F/TAF superior to

E/C/F/TDF

STARTMRK(n=566)15:

RAL + TDF/FTC

non-inferior to

EFV+TDF/FTC

SPRING-2 study(n=822)2:

DTG+2NRTI non-inferior to

RAL+2NRTI

1490 study(n=600)7:

B/F/TAF non-inferior to

DTG+FTC/TAF

102 study(n=700)11:

E/C/F/TDF non-inferior to

EFV/FTC/TDF

FLAMINGO study(n=484)3:

DTG+2NRTI superior to

DRV/r+2NRTI

Tx patients

SAILING study4:

DTG+OBR superior to

RAL+OBR

1878 study(n=520)8:

Switching to B/F/TAF non-

inferior to SBR(boosted

PI+2NRTIs)

109 study(n=1436)12:

Switching to E/C/F/TAF

superior to continuing

FTC/TDF + 3rd agent

BENCHMRK-1 & -2

study(n=703)16:

RAL + OBR superior to

Placebo+OBR

VIKING-3 study5:

RAL/EVG resistant Patients

1844 study(n=520)9:

Switching to B/F/TAF non-

inferior to

SBR(DTG/3TC/ABC)

Special population:

Study 106(n=50)13: 12-18 yrs

adolescent

Study 112(n=242)14: eGFR

30-69 ml/min

1. Raffi F, et al. Lancet 2013;381:735–43 2. Walmsley S, et al.N Engl J Med 2013;369:1807–18 3. Clotet B, et al.Lancet 2014;383:2222–31 4. Cahn P, et al. Lancet 2013;382:700–8 5. Castagna A, et al. J Infect Dis 2014;210:354–62 6. Gallant J, et al. Lancet 2017;390:2063-72. 7.Sax P, et al. Lancet 2017;390:2073-82. 8. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4.9. Molina JM, et al. CROI 2018. Boston, MA. Oral 22. 10.Sax P, et al. J Acquir Immune Defic Syndr 2014;67:52–8; 11. Sax PE et al. Lancet 2012;379:2439–2448; 12. Mills A, et al. Lancet Infect Dis 2016; 16:43-52 13. Gaur A, et al. CROI, 2016. Boston, MA #817 14.Pozniak A, et al. JAIDS 2016;71(5):530-7 15. Lennox JL et al. Lancet 2009;374:796–806;

16. Steigbigel RT et al. N Engl J Med 2008;359:339–354

1 Walmsley SL1, Antela A, Clumeck N et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.N Engl J Med. 2013 Nov 7;369(19):1807-18. 2 Walmsley S1, Baumgarten A, Berenguer J, et al. Brief Report: Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week 144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr 2015;70:515–519. 3 Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the randomised open-label phase 3b study.Lancet. 2014 Jun 28;383(9936):2222-31. 4 Molina JM, Clotet B, van Lunzen J et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomised, open-label, phase 3b study. Lancet HIV. 2015 Apr;2(4):e127-36.

High virological response rate at week 4 is a good predictor for long-term HIV replication inhibition.

For treatment-naïve patients, rapid suppression of HIV replication is cost-effective.

INIs can rapidly suppress HIV RNA replication

FLAMINGO3,4 study:

DTG+2NRTIDRV/r +2NRTI

E/C/F/TDFEFV/FTC/TDF

1489 and 1490 study:

102 study:Sping 2 study:

DTG+2NRTIRAL+2NRTI

Rapid decrease of viral load is associated with improved control of immune activation.

Notes: edited from original figure

Pro

po

rtio

n o

f a

ctiva

ted

CD

8+

T c

ells

（%

）

P=0.034

P=0.004P=0.040

• CD8+ T cell activation is the strongest predictor of AIDS progression. Reduced CD8+ T cell activation

is associated with better immune reconstitution and thus is likely to impact the patients’ ability to limit

opportunistic infection.

• The time needed to undetectable viral load was 4 months in patients with early control of HIV-RNA and

10 months for those with late control.

• One hundred and thirty-five HIV-1 Mozambican adults initiating cART were prospectively followed and

plasma HIV-RNA, CD4+ counts, and CD8+ T cell activation were monitored at the pre-cART visit and at

4, 10, and 16 months during cART.

CD8+ T cell activation was more suppressed in patients with early control of HIV-RNA.

13.Almeida JM, Letang E, Nhampossa T,et al.Rapid Suppression of HIV-RNA Is Associated with Improved Control of Immune Activation in Mozambican Adults Initiating Antiretroviral Therapy with Low CD4 Counts. AIDS Res Hum Retroviruses. 2011;27(7):705-11.

Rapid decrease of viral load helps persistent suppression of HIV replication.


Pro

po

rtio

n o

f p

atie

nts

with

rea

pp

ea

ran

ce

of d

ete

cta

ble

HIV

-RN

A （

%）

P=0.001

• Early virological controllers experienced reduced risk of reappearance of

detectable HIV-RNA at 6 months postcontrol as compared to late HIV

controllers (P=0.001).

Notes: plotted based on original data

• The time needed to undetectable viral load was 4 months in patients with early control of HIV-RNA and

10 months for those with late control.

• One hundred and thirty-five HIV-1 Mozambican adults initiating cART were prospectively followed and

plasma HIV-RNA, CD4+ counts, and CD8+ T cell activation were monitored at the pre-cART visit and at

4, 10, and 16 months during cART

Delayed HIV-RNA suppression increase the risk of drug resistance.

Rapid and persistent suppression of HIV-RNA is a key

successful factor

10.彭志行,鲁佳菲,王岚,等.中国艾滋病抗病毒治疗的流行病学研究.中华流行病学杂志 2012,33(9):977-982


Patients with delayed HIV-RNA suppression are in a state of

suboptimal cART treatment which would allow HIV to replicate

for a longer lapse of time than in early virological controllers,

thus increasing the opportunity for the development of resistance.








patients 4,5





‡

Dissociation Kinetics & In Vitro Resistance Profile andG140S+Q148H Mutant Integrase-DNA Complexes1

211. White K, et al. CROI 2017. Seattle, WA. Poster #497. 2. Hightower K, et al. Antimicrob Agents Chemo 2011;55(10):4552-4559.

‡

Mean Dissociation Half-life (hours)

Wild Type G140S+Q148H

• BIC has >2 and >3 times longer dissociation T1/2 from wild-type and G140S+Q148H mutant integrase-DNA complexes compared to DTG, respectively

EC, effective concentration; FC, fold change; ND, not detected; T1/2, half-life

INSTI

Fold-

Change

vs WT*

% of Isolates

with EC50 FC

> 4.0

P-value

vs BIC

RAL >143 100% <0.001

EVG >150 100% <0.001

DTG 7.6 ± 4.3 75% <0.001

BIC 3.4 ± 1.7 75% --

INSTI

Fold-

Change

vs WT*

% of Isolates

with EC50 FC

≤ 4.0‡

P-value

vs BIC

RAL >143 0% <0.001

EVG >150 0% <0.001

DTG 7.6 ± 4.3 25% <0.001

* Patient-derived clinical isolates with INSTI-R (Monogram Biosciences).† Mean ± standard deviation.‡ The lower clinical cut-off for reduced susceptibility to DTG on the PhenoSense IN assay is 4-fold.

Phenotypic Analysis of Clinical Isolates*G140S + Q148H ± Other INSTI-R (n=16)

• BIC has more potent antiviral activity

against G140S/Q148H integrase

mutants vs DTG

ND ND

‡

Patient Isolates with INSTI Resistance Mutations: Resistance Profile of BIC and Other INSTIs

22

Phenotypic Analysis of Clinical Isolates

1. White K, et al., European Workshop HIV & Hep 2016. Rome, Italy. Poster O-01. 2. Tsiang M, et al., AAC 2016;60:7086-7097.

BIC has a statistically improved resistance profile compared to RAL, EVG, and DTG

Mean fold changes: BIC 2.8 (ref) ; DTG 5.8, p=0.042; RAL >100, p<0.001; EVG >106, p<0.001

Each of 47 patient-derived clinical isolates (from Monogram Biosciences) had ≥ 1 primary and/or other INSTI mutations with phenotypic resistance to INSTIs and comprised all available INSTI resistant variants in the Monogram library).

Stratification of 47 HIV-1 Clinical Isolates Based on Fold Change in Resistance

< 2.5 ≥ 102.5 to < 5 5 to < 10

EC50 Fold Change (FC) vs Reference Wild Type

EC50=effective concentration of half maximal response; FC=fold change; IN=Integrase; T1/2=half-life.

‡

BIC or EVG < 2.5RAL <1.5DTG <4

BIC or EVG ≥ 10RAL >10DTG >13

BIC or EVG 2.5-10RAL 1.5-10DTG 4-13

Bictegravir has a Favorable Cross-Resistance Profile

Comparison of INSTI cross-resistance using a representative panel

of HIV with integrase mutants from clinical isolates and site directed mutations

Single Primary Mutations

IN GenotypeFold Change vs WT

BIC DTG EVG RAL

E92Q 1.2 1.6 60 18

T97A 0.7 0.9 10 1.8

F121Y* 0.4 0.6 16 5.3

Y143C* 0.9 0.9 2.2 4.3

Y143R 1.4 1.4 2.2 16

Q148H* 0.7 0.8 8.7 4.3

Q148K* 0.8 0.7 108 43

Q148R* 0.7 0.7 117 40

N155H* 1.4 1.5 41 17

R263K* 1.7 1.7 4.5 1.2

More Complex Resistance Patterns

IN GenotypeFold Change vs WT

BIC DTG EVG RAL

T97A, N155H 1.0 1.5 95 53

E138K, Q148R 1.7 2.2 >150 54

G140A, Q148R 2.0 2.2 >150 88

G140S, Q148H 2.5 5.6 >150 >143

G140S, Q148H, G163K 2.5 5.7 >150 >143

L74M, G140C, Q148R 8.4 9.1 >150 >143

T97A, G140S, Q148H 4.4 15 >150 >143

E138K, G140S, Q148H 2.5 5.3 >150 >143

E138A, G140S, Q148H 7.2 10 >150 >143

E138K, G140A, Q148K 19 63 >150 >143

Tsiang et al, Antimicrobial Agents and Chemotherapy, 2006

Andreatta K et al. CROI 2018. Boston, MA. Poster #546

White K, et al . CROI 2018. Boston, MA. Poster 532

Gilead Sciences. Data on File23

BIC resistance in vitro is possible but requires complex resistance patterns

* Site directed mutants

NO RESISTANCE TO DTG+2NRTIS IN TREATMENT-NAÏVE TRIALS 1– 4

1. Raffi F et al. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96

week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2013;13:927–935; 2. Walmsley SL et al. Brief Report:

Dolutegravir Plus Abacavir/Lamivudine for the Treatment of HIV-1 Infection in Antiretroviral Therapy-Naive Patients: Week 96 and Week

144 Results From the SINGLE Randomized Clinical Trial. J Acquir Immune Defic Syndr 2015;70:515–519;

3. Molina JM et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96

week results from a randomised, open-label, phase 3b study. Lancet HIV 2015;2:e127–e136; 4. . Orrell C,et al. Fixed-dose combination

dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and emtricitabine in

previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b

study.Lancet HIV. 2017 Jul 17.

DTG exhibited high resistance barrier in the clinical studies

SPRING-21

(to week 96)*SINGLE2

(to week 144)*FLAMINGO3

(to week 96)†ARIA4

(to week 48)

DTG 50 mg

QD(N=411)

RAL 400 mg

BID(N=411)

DTG 50 mg + ABC/3TC

QD(N=414)

EFV/TDF/FTC QD

(N=419)

DTG 50 mg

QD(N=242)

DRV/r 800/100 mg QD (N=242)

DTG/ABC/3TC QD

(n=248)

ATV/r QD + TDF/FTC

QD (n=247)

22 (5) 29 (7) 39 (9) 33 (8) 2 (<1) 4 (2) CVW:¶ 6 CVW:¶ 4

0 1 (6)‡ 0 0 0 0 0 0

0 4 (21)‡§ 0 1 (K65K/R) 0 0 0∥ 1

– – 0

6 (K101E,

K103K/N, G190G/A)

– – 0 0

– – 0 0 0 0 0 0

N (%)

PI-耐药突变

NNRTI-耐药突变

NRTI-耐药突变

INI-耐药突变mutations

PDVF患者

‡

B/F/TAF Phase 3 Efficacy through Week 48

25

Study Population Comparator Efficacy Resistance

14891 Naïve DTG/ABC/3TC Non-inferior* 0

14902 Naïve DTG+FTC/TAF Non-inferior* 0

18443 Suppressed DTG/ABC/3TC Non-inferior† 0

18784 Suppressed Boosted PI + 2 NRTIs Non-inferior† 0‡

19615 SuppressedE/C/F/(TAF or TDF)

ATV+RTV + FTC/TDFNon-inferior† 0**

* For ART-naïve studies: Treatment outcomes [between treatment groups] were similar across subgroups by age,

sex, race, baseline viral load, and baseline CD4+ cell count.6

† For virologically suppressed studies: Treatment outcomes between treatment groups were similar across

subgroups by age, sex, race, and region.5,6

‡ One boosted PI regimen participant on DRV+RTV+ABC/3TC developed ABC mutation L74V

** One E/C/F/TAF participant developed FTC mutation M184M/I/V

1. Gallant J, et al. Lancet 2017;390:2063-72.2. Sax P, et al. Lancet 2017;390:2073-82.3. Molina JM, et al. CROI 2018. Boston, MA. Oral 22

In five Phase 3 trials of 1,440 patients through Week 48

B/F/TAF had non-inferior efficacy with zero emergent resistance

4. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4

5. Kityo C, et al. CROI 2018. Boston, MA. Poster 500.

6. Gilead Sciences. Biktarvy US Prescribing Information. February 2018.

‡Rationale for high-barrier resistance of DTG and BIC:Trough exposures are well-above of the protein-adjusted 90% inhibitory concentration (PA-IC90).

Me

an

pla

sm

a c

on

ce

ntr

ation o

f 5

0 m

g o

f

DT

G (

μg/m

L)

Drug resistance barrierDTG 50mg QD

给药后时间（小时）

Trough plasma

concentrations of DTG 50

mg QD is 19 folds1 of paIC90.

1. van Lunzen J, Maggiolo F, Arribas JR, et al. Lancet Infect Dis. 2012 Feb;12(2):111-8. 2.Gilead Sciences. Biktarvy US Prescribing Information. February 2018

Trough plasma

concentrations of DTG

50 mg QD is 16.1 folds2

of the paEC95

streamlined architecture

stronger binding to HIV

integrase than RAL and

EVG.

Prolonged binding to HIV

integrase and following

inhibition inhibits integrase

activation and reduces the

chance of mutation.

better adapted to conformation changes

due to mutations

The length and flexibility of the structure favors

stronger binding potency to RAL/EVG-resistant IN

enzymes.

Rationale for high resistance barrier of DTG and BIC:The streamlined architecture of metal-chelating scaffold is the structural basis.

DeAnda F, et al. Dolutegravir interactions with HIV-1 integrase-DNA: structural rationale for drug resistance and dissociation kinetics. PLoS ONE 2013;8(10):e77448

Dolutegravir Bictegravir








patients 4,5





1. Walmsley S, et al. Dolutegravir plus abacavir-lamivudine for the treatment of HIV-1 infection.N Engl J Med 2013;369:1807–182. clotet B, et al. Once-daily dolutegravir versus darunavir plus ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week results from the

randomised open-label phase 3b study.Lancet 2014;383:2222–313. Orrell C,et al. Fixed-dose combination dolutegravir, abacavir, and lamivudine versus ritonavir-boosted atazanavir plus tenofovir disoproxil fumarate and

emtricitabine in previously untreated women with HIV-1 infection (ARIA): week 48 results from a randomised, open-label, non-inferiority, phase 3b study.Lancet HIV. 2017 Jul 17.

4. Raffi F, et al. Once-daily dolutegravir versus raltegravir in antiretroviral-naive adults with HIV-1 infection: 48 week results from the randomised, double-blind, non-inferiority SPRING-2 study. Lancet 2013;381:735–43

DTG-based regimen and other regimensDiscontinuation Rates due to AEs through Week 48

EFV/TDF/

FTC QD(n=419)

DTG QD + 2

NRTIs QD

(n=411)

RAL BID + 2 NRTIs

QD(n=411)

DTG QD + 2

NRTIs QD

(n=242)

DTG QD +

ABC/3TC QD

(n=414)

DRV/r QD + 2 NRTIs QD

(n=242)

DTG/ABC/3TC

QD (n=248)

ATV/r QD +

TDF/FTC QD

(n=247)

2% 2%

4%

2%

10%

4%

7%

2%

SINGLE 48 weeks1 FLAMINGO

48 weeks2

SPRING-248 weeks4

ARIA 48 weeks3

Dis

con

tin

uati

on

s b

eca

use

of

ad

vers

e e

ven

ts （

%）

‡

B/F/TAF and DTG-based regimenDiscontinuation Rates due to AEs through Week 48

1. Gallant J, et al. Lancet 2017;390:2063-72.2. Sax P, et al. Lancet 2017;390:2073-82.3. Molina JM, et al. CROI 2018. Boston, MA. Oral 22

4. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-4

5. Kityo C, et al. CROI 2018. Boston, MA. Poster 500

6. Gaur A, et al. CROI 2018. Boston, MA. Poster 844

B/F/TAF and DTG-based regimen are both well tolerated overall discontinuation due to AEs through 48 weeks

*Study 1474 adolescent primary outcomes are from Week 24

30

Comparator: DTG/ABC/3TC DTG/ABC/3TCDTG+FTC/TAF Boosted PI+ 2 NRTIs

E/C/F/TAF or TDF, ATV+RTV+FTC/TDF

31

B/F/TAF vs. DTG-based Regimens: Drug-Related Adverse Events through Week 48

1. Gilead Sciences. Biktarvy US Prescribing Information. February 20182. Gallant J, et al. Lancet 2017;390:2063-72.3. Sax P, et al. Lancet 2017;390:2073-82.4. Molina JM, et al. CROI 2018. Boston, MA. Oral 22. 5. Gilead Sciences. Data on File.

Significantly fewer drug-related AEs with B/F/TAF in all 3 randomized, double-blinded comparisons

to DTG based regimens through Week 48

B/F/TAF Registrational Studies

p<0.0015 p=0.0223 p=0.014

*B/F/TAF participants had significantly less drug-related nausea compared to DTG/ABC/3TC (5% vs 17%; p<0.0001)2

ART-Naive VirologicallySuppressed

‡

Drug-Related Adverse Events (AEs) through Week 48

32

Study 1489 & 1844: B/F/TAF vs DTG/ABC/3TC in ART-Naïve and Suppressed Adults

Study 14891

All grade

(≥ 2% in either arm)

B/F/TAF

n=314

DTG/ABC/3TC

n=315

Any Drug-related AEs 26%* 40%

Diarrhea 6% 4%

Nausea 5%† 17%

Headache 5% 5%

Fatigue 3% 3%

Abnormal dreams 3% 3%

Dizziness 2% 3%

Insomnia 2% 3%

Study 18442

All grade

(≥ 1% in either arm)

B/F/TAF

n=282

DTG/ABC/3TC

n=281

Any Drug-related AEs 8%** 16%

Headache 3% 3%

Abnormal dreams <1% 2%

Diarrhea <1% 1%

Fatigue <1% 1%

Flatulence 0% 2%

Nausea 0% 2%

Insomnia 0% 1%

B/F/TAF was well tolerated with significantly fewer drug-related AEsthan DTG/ABC/3TC in ART-naïve and suppressed patients,

largely due to GI and CNS AEsB/F/TAF

Difference between treatment arms: * p<0.0013, † p<0.0001, and ** p=0.01

1. Gallant J, et al. Lancet 2017;390:2063-722. Molina JM, et al. CROI 2018. Boston, MA. Oral 223. Gilead science. Data on File.

33

B/F/TAF DTG/ABC/3TC

B/F/TAF in Treatment-Naïve & Suppressed Adults

B/F/TAF vs DTG/ABC/3TC: Similar and minimal impact on BMD through Week 48 in ART-naïve and suppressed studies1-2

No discontinuations due to bone toxicities in B/F/TAF development program1-6

HipSpine

B/F/TAF vs DTG/ABC/3TC: Similar and minimal impact on BMD

p=0.33

p=0.47

24 48

Weeks

0 24 48

Weeks

0

0.690.42 0.30

0.16

Stu

dy 1

48

9S

tud

y 1

84

4

Me

an

% C

ha

ng

es

fro

m B

as

eli

ne

(95

% C

I)

24 48

Weeks

0 24 48

Weeks

0

5. Kityo C, et al. CROI 2018. Boston, MA. Poster 5006. Gaur A, et al. CROI 2018. Boston, MA. Poster 844

3. Sax PE, et al. Lancet. 2017;390:2073-2082

4. Daar E, et al. IDWeek 2017. San Diego, CA. Oral LB-4

1. Gallant J, et al. Lancet 2017;390:2063-722. Molina JM, et al. CROI 2018. Boston, MA. Oral 22

-1.02%-0.78%

2

1

0

-1

-2

-0.60%

-0.83%

2

1

0

0

-1

-2

0

Similar changes in renal biomarkers Quantitative Proteinuria for B/F/TAF and ABC/3TC regimens

34

Med

ian

% C

han

ge

fro

m B

ase

lin

e

Study 1878*,3

B/F/TAF in Treatment-Naïve and Virologically-Suppressed Adults

* Study 1878: P-values were not calculated by baseline regimen type, however the overall

dataset had significant improvements in RBP:Cr and β2M:Cr on B/F/TAF vs boosted PI

regimens with ABC/3TC (15%) or FTC/TDF (85%) (p<0.001) and no difference in UACR.

1. Gallant J, et al. IAS 2017. Paris, France. Oral #MOAB0105LB 2. Gallant J, et al. Lancet 2017;390:2063-723. Daar E, et al. ID Week 2017. San Diego, CA. Oral LB-44. Molina JM, et al. CROI 2018. Boston, MA. Oral 22

Study 14891,2

Similar changes in renal biomarkers for B/F/TAF and ABC/3TC regimens in ART-naïve and suppressed studies

No B/F/TAF discontinuations due to renal adverse events and no proximal tubulopathy

Study 18444

β2M:CrRBP:CrUACRβ2M:CrRBP:CrUACR

p=0.11

p=0.34

p=0.40

β2M:CrRBP:CrUACR

p=0.74

p=0.31

p=0.53

p-values: not calculated*

β2M: beta-2-microglobulin, Cr: creatinine, RBP: retinol binding protein, SBR: stayed on baseline regimen, UACR: urine albumin to creatinine ratio.

Boosted PI + ABC/3TC

B/F/TAF DTG/ABC/3TC

HIV backbone for Renally Impaired Patients

▪ TAF-based antiretrovirals are approved for HIV infection in patients with creatinine clearance of ≥30 mL/min, which is an improvement over TDF-based antiretrovirals.

▪ Vemlidy (TAF 25mg) is approved for HBV infection in patients with creatinine clearance of ≥15 mL/min.

▪ TRIUMEQ is not recommended for use in patients with a CrCl < 50 ml/min

FDA Approved Creatinine Clearance Cut-offs (eGFR, L/min)

F/TAF-based Antiretrovirals F/TDF or TDF-based Antiretrovirals ABC/3TC

Descovy

FTC/TA

F(25 mg)

Odefsey

R/F/TA

F(25 mg)

Genvoya

E/C/F/TA

F(10 mg)

Bictarvy

B/F/TAF(25mg)

Viread

TDF300

mg

Truvada

FTC/TD

F(300 mg)

Complera

R/F/TDF(300 mg)

Stribild

E/C/F/T

DF(300 mg)

Triumeq

ABC/3TC/D

TG (

600mg/300mg)

≥30 ≥50 ≥70 ≥50

US Prescribing Information: Bictarvy 2018, Vemlidy 2017, Viread 2017, Genvoya 2017, Complera 2017, Odefsey 2017, Descovy 2017, Stribild 2017, Truvada 2017

‡

35

• The risk for potential drug-drug interactions

increased in older patients who take more drugs

than their younger HIV-infected counterparts.

A Swiss prospective cohort study showed older HIV-

infected patients (≥50) were more likely to receive one or

more co-medications compared with younger patients

(82% versus 61%; P<0.001) and to use at least one kind

of non-antiretroviral drugs, thereby with more frequent

drug-drug interactions.

1.蔡卫平, 张复春, 唐小平,等. 艾滋病并发症临床分析[J]. 中国艾滋病性病, 2002, 8(3):142-144 2.Marzolini C, Back D, Weber R, et al. Ageing with HIV: medication use and risk for potential drug-drug interactions. J Antimicrob Chemother. 2011 Sep;66(9):2107-11

Pro

po

rtio

n o

f

pa

tie

nts

（%

）

Number of other drugs taken

Concomit

ant

diseases

with AIDS

Opportunistic

infections

Digestive

diseases

Hepatitis

（HBV/HCV）

Cardiovascular

diseases

Respiratory

diseases

CNS diseases,

hematopathy,

drug over-

use, and et al.

86.6% of Chinese HIV/AIDS patients are complicated with

multi-system diseases 1 which is related with increased

combinatorial drugs use leading to decreased anti-HIV

efficacy and increased toxic and side effects.

• Comorbidities are frequently

seen in AIDS patients

More attention should be paid to drug-drug interactions.

years

years

https://www.ncbi.nlm.nih.gov/pubmed/21680580

https://www.ncbi.nlm.nih.gov/pubmed/21680580

DDI with Anaesthetics and Muscle Relaxants

1. University of Liverpool. Drug interactions chart. June 2015. http://www.hiv-druginteractions.org. Accessed July 6, 2015. 2. Shah B M, Schafer J J, Priano J, et al. Cobicistat: a new boost for the treatment of human immunodeficiency virus infection.Pharmacotherapy, 2013, 33(10): 1107-1116.

B/F/TAF DTG EFV E/C/F/TAF LPV/r RAL

DDI with Analgesics


Safety


DDI with Anti-diabetics


Safety


DDI with Antibacterials


Safety









patients 4,5





Palatability, Acceptable tablet size and shape

42

▪ Patient compliance with medication regimens may be influenced by the size and shape

of a tablet or capsule, with size frequently being cited as the main reason for the difficulty

in swallowing3

Tablet Appearance

E/C/F/TAF (1082 mg)

DTG/ABC/3TC (1750 mg)

B/F/TAF (721 mg)

Number in parenthesis is the total weight in mg of the tablet. Note: Tablet size is not intended to compare clinical efficacy and safety, indications, dosing regimens, or treatment adherence.

DTG/ABC/3TC, dolutegravir/abacavir/lamivudine; B/F/TAF, bictegravir/emtricitabine/tenofovir alafenamide; E/C, elvitegravir/cobicistat; INSTI, integrase strand transfer inhibitor

1. Gilead Sciences. Data on File.

2. Gilead Sciences. Biktarvy US Prescribing Information. February 2018

3. DHHS & FDA CDER. Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules. June 2015

The convenience of taking the drug

Studies have found once daily dosing improves adherence to antiretroviral therapy 1 and

the risk of in nonadherence decreased by 53%. 8

Once dailyNo food requirement

No time requirement

No PK enhancer

note

B/F/TAF5 √ √ √ √Anti-HBV （advantages and

disadvantages）

DTG/ABC/3TC1 √ √ √ √ HLA-B5701

E/C/F/TAF2 √ × √ ×

Anti-HBV（advantages and disadvantages）

RAL3

× √ √ √ Twice daily，no STR

EFV4

√ × × √Taken before sleep on an

empty stomach（recommended）

LPV/r6X

Taken simultaneously with

foodX × Taken after meal (required）

1 TRIUMEQ 说明书. 2 Vitekta 说明书 3 Isentress 说明书 4 Atripla 说明书 5 Biktarvy US PI. 6 Kaletra 说明书 7 PREZCOBIX 说明书

Contents




20 Years of Progress in HIV Treatment & Prevention

45

(for HIV)

(for PrEP)

DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. February 2002 and October 2017. http://aidsinfo.nih.gov/guidelines

2004 2012 2016 20181996 2000 2008 20142010200620021998

20 Years of Progress in HIV Treatment & Prevention

46

2004 2012 2016 2018

(for HIV)

(for PrEP)

1996 2000 2008 20142010200620021998

• Pill burden • Fixed dose combinations• Food requirement• Drug interactions• Genetic barrier to resistance• HBV and/or HCV coinfection• eGFR limitations

DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. February 2002 and October 2017. http://aidsinfo.nih.gov/guidelines

February 2002

•May be difficult to adhere to•Long-term side effects•Low genetic barrier•Long-term high BL VL efficacy suboptimal

October 2017• Hypersensitivity reactions• Renal and bone limitations• Hepatic impairment• Psychiatric illnesses• Cardiovascular risk• HLA-B*5701• Lipids

Recommended Initial Regimens for Most People with HIV

DHHS Guidelines 2018

DHHS. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Available at: http://aidsinfo.nih.gov/guidelines October 2017.

DHHS Statement on the Use of Bictegravir, March 27, 2018. Available at: http://aidsinfo.nih.gov/guidelines

CLASS RECOMMENDED REGIMEN

Integrase Inhibitor

BIC/FTC/TAF*† (AI)

EVG/COBI/FTC/TAF† (AI)EVG/COBI/FTC/TDF† (AI)

DTG/3TC**/ABC‡ (AI)

DTG +

FTC/TAF† (AI) or FTC**/TDF† (AI)

RAL§

+FTC/TAF† (AII) or FTC**/TDF† (AI)

* Not for creatinine clearance <30 mL/min, severe liver impairment, persons younger than 18 years of age, and there is insufficient safety information regarding

use in pregnant women.

† TAF and TDF are two forms of tenofovir approved by FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels.

Safety, cost and access are among the factors to consider when choosing between these drugs.

**3TC may substitute for FTC or vice versa

‡ Only for HLA-B*5701 negative

§ RAL can be given as 400 mg BID or 1200 mg (two 600-mg tablets) once daily

• Only integrase inhibitor-based regimens are recommended as initial

regimens for “Most People with HIV”

http://aidsinfo.nih.gov/guidelines

http://aidsinfo.nih.gov/guidelines

Conclusion

Long-term HIV treatment:

The selection Initial Antiretroviral Regimen is crucial.

Integrase inhibitors, especially the INIs-based STRs, have potent virological

response and better tolerance, are the standard recommended treatment regimen

currently for most of the naïve patients.

Each integrase inhibitor has its own charateristics, provide the optimal choice

for different patient population.

THANK YOU

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