Clinical and Therapeutic aspects of HIV Sabine Kinloch, MD Royal - - PowerPoint PPT Presentation

Clinical and Therapeutic aspects of HIV

Sabine Kinloch, MD Royal Free Hospital UCL partners University College Medical School London, UK

ISHEID 2014

Conflict of interest

Travel grants from Gilead and BMS European Union research grant AMFAR grant

Acknowledgments

The ISHEID speakers for kindly providing their slides

Summary

• Unable to cover all presentations
• ART 2014: state of art, potency, resistance

drug development pipeline

• Eradication paradigm

ART 2014

• Multiple compounds available-LT toxicity-

adherence-aging population-comorbidities-R

• Newer compounds
• Robust pipeline of new drugs (all classes)
• Potency and resistance revisited
• Gene therapy
• Eradication

ART 2014

• Co-morbidities: choice of ART, CV, diabetes,

bone, kidney

• Long-term treatment with aim of (no) or two

development of resistance, decrease of side-effects (short and long-term)

• LT Adherence: new ART strategies and drugs
• ART for resource-limited countries,

children/adolescents

• Effect of ART on the epidemic ………….and costs

and ……generics

ART 2014

• Multiple compounds available
• Exciting pipeline
• Long-term toxicity
• Adherence: treatment for decades
• Ageing population
• Comorbidities

Other Classes

Fusion inhibitors

• Enfuvirtide

R5 Inhibitors

• Maraviroc

Integrase Inhibitors

• Raltegravir
• Elvitegravir
• Dolutegravir

Protease Inhibitors

Atazanavir Darunavir Fos-Amprenavir Indinavir Lopinavir Nelfinavir Ritonavir Saquinavir Tipranavir

NNRTIs

Efavirenz Nevirapine Etravirine Rilpivirine

Available Antiretrovirals 2014= 25

NRTIs

Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine

STR

Atripla Eviplera Stribild

Adapted from: 1. Lennox JL, et al. Lancet 2009;374:796−806. 2. Riddler SA, et al. N Engl J Med 2008;358:2095–106. 3. Sierra-Madero J, et al. JAIDS 2010;53:582–8. 4. Molina J-M, et al. Lancet 2008;372:646–55. 5. Molina J-M, et al. JAIDS 2010;53:323–32. 6. Ortiz R, et al. AIDS 2008;22:1389–97. 7. Mills AM, et al. AIDS 2009;23:1679─88; 8. Martínez E, et al. CROI 2013. Oral presentation 772. URL: http://www.retroconference.org/2013b/Abstracts/47369.htm. 9. Gallant JE, et al. JID 2013 [Epub ahead of print]. 10. DeJesus E, et al. Lancet 2012;379:2429–38. 11. Sax PE, et al. Lancet 2012;379:2439–48. 12. Soriano V, et al. Antivir Ther 2011;16:339–48. 13. Daar ES, et al. Ann Intern Med 2011;154:445–56. 14. van Leth F, et al. Lancet 2004;363:1253–63. 15. Molina J-M, et al. Lancet 2011;378:238–46. 16. Cohen CJ, et al. Lancet 2011;378:229–37. 17. European Medicines Agency http://www.ema.europa.eu (Accessed Apr 2013). 18. ATRIPLA SmPC Available at: http://www.ema.europa.eu Last updated 12/02/2013 (Accessed Apr 2013). 19. Raffi et al. Lancet. 2013;381:735-43. 20. Walmsley S, et al. ICAAC 2012, San Francisco, USA. Oral abstract H-556b http://www.natap.org/2012/ICAAC/ICAAC_06.htm.

• 21. Cohen C et al. HIV11 2012. Oral presentation O425. URL: http://natap.org/2012/interHIV/InterHIV_15.htm. 22. Feinberg J et al. ICAAC 2013. Abstract H-1464a. http://www.icaaconline.com/php/icaac2013abstracts/start.htm.

PI NNRTI INSTI

…a potent armamentarium

Large head to head study Small head to head study

*EFV/FTC/TDF is not licensed for use in antiretroviral naive patients in Europe17,18 ** ATV/c is not yet licensed for use in HIV-infected patients in Europe

Europe

NVP ATV/r

CASTLE,4,5 ACTG 520213

LPV/r EFV DRV/r

EVG/c

Study 10310

ATV/c**

ATADAR8

RAL

STARTMRK1

RPV

ECHO15 THRIVE16 STAR21 2NN14

DTG†

SPRING-219 FLAMINGO22

Up to 90% of treatment-naive patients can now achieve undetectable HIV-1 RNA1-16

Drug / class FDA approval Toxicity Strong signal Delay (years) Zidovudine1 1987 Lipoatrophy 1999 12 Stavudine 1 1994 Lipoatrophy 1999 5 Nevirapine 1996 Hepatitis / rash at higher CD4 2005 9 PIs2 1996- Heart attack 2003 7 Efavirenz3 1998 Suicidality 2013 15 Tenofovir4 2001 Kidney disease 2006 5 Tenofovir5 2001 Fracture 2013 12 Raltegravir6 2007 Myopathy 2012 5

• 1. Saint-Marc T et al, AIDS 1999;13:1659–1667. Cross-sectional, multicentre study. N=43. 2. Friis-Mollen N et al, N Engl J Med 2003;349:1993–2003. Prospective
• bservational study. N=23,468. 3. Mollan et al, IDSA 2013;abstract 670. Cross-study analysis. N=5332 ARV-naive patients (4 studies). 4. Cooper RD et al, Clin Infect Dis

2010; 51:496–505. Meta-analysis of 17 trials (9 RCTs) 5. Bedimo R et al, AIDS 2012;26:825–831. Retrospective analysis. N=56,600. 6. Lee FJ et al, J Acquir Immune Defic Syndr 2013;62:525–533. Cross-sectional, 2-arm prevalence study. N=318.

Toxicities: delayed recognition

• 12%

+12%

• 1.1

4.1 9.2 4.2 10.3

• 1.9
• 1.6

3.6 8.8 5.1 9.4 0.7 2.5 7.4 12.3 1.1 7.2 13.4 9.5 17.3 1.7

Efficacy: newer treatments outperform EFV

Favours EFV Favours Comparator

GS-1021 (STB vs. ATR) N=700 88% vs. 84% (Snapshot) GS-102/103/1042 (STB vs. ATR) N=1124 89% vs. 84% (Snapshot) STaR3 (CPA vs. ATR) N=786 86% vs. 82% (Snapshot) 89% vs. 82% (Snapshot) BLVL ≤100,000 cpm STARTMRK4 (RAL vs. EFV) N=566 86% vs. 82% (ITT, NC=F) 71% vs. 61% (ITT, NC=F) SINGLE5 (DTG vs. ATR) N=833 88% vs. 81% (Snapshot)

Newer ARVs have demonstrated higher rates of virologic suppression compared to EFV-based regimens in HIV-1 infected ART-naïve patients

Week 48: Non-inferiority shown Week 48 (Pooled): Statistically significant higher VL response Week 48: Non-inferiority shown Week 48: Statistically significant higher VL response Week 48: Statistically significant superior VL response Week 48: Non-inferiority shown Week 240: Statistically significant higher VL response

1. Sax P, et al. Lancet 2012;379:2429–38 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File 4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 6. Cohen C, et al. JAIDS 2012;60:33-42

ECHO/THRIVE6 (RPV vs. ATR) N=1368 83% vs. 80% (Snapshot) 90% vs. 84% (TLOVR) BLVL ≤100,000 cpm

• 1.7

2.4 6.6 1.6 6.6 11.5 Week 48: Non-inferiority shown Week 48: Statistically significant higher VL response

Differences in Percentages (95% CI)

• 5
• 10
• 15
• 20

20 15 10 5

ACTG 5257

• atazanavir, raltegravir and darunavir

virologically equivalent in naive patients but significant differences for tolerability

Phase III DTG trials in treatment-naïve ADULT subjects with HIV

*Given as 2 x 400 mg tablets NRTI, nucleoside reverse transcriptase inhibitor DRV/r, darunavir/ritonavir; QD, once daily; BID, twice daily; FDC, fixed-dose combination

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of:

• DTG (50 mg QD) plus RAL placebo (BID) + 2 NRTIs
• RAL (400 mg BID) plus DTG placebo (QD) + 2 NRTIs

SPRING-23,4 N=822

Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of:

• DTG (50 mg QD) with ABC/3TC FDC plus EFV/TDF/FTC FDC

placebo

• EFV/TDF/FTC FDC (QD) plus DTG and ABC/3TC FDC placebo

SINGLE1 N=833

Phase IIIb non-inferiority, randomised, active-controlled, multicentre,

• pen-label study of:
• DTG (50 mg QD) + 2 NRTIs
• DRV/r (800 mg*/100 mg QD) + 2 NRTIs

FLAMINGO2 N=484

1. Walmsley S et al. N Engl J Med 2013;369:1807-1818 2. Clotet B, et al. Lancet 2014 March 31 [Epub ahead of print] 3. Raffi F et al. Lancet 2013;381:735–43 4. Raffi F et al. Lancet 2013. doi.org/10.1016/S1473-3099(13)70257-3

14



At Week 96: DTG + ABC/3TC was superior to EFV/FTC/TDF. Statistically higher response driven by withdrawals for AEs: 3% (DTG arm) vs. 11% (EFV arm)



Protocol-defined VFs (confirmed ≥ 50 copies/mL at or after W24) were identical in both arms at Weeks 48 (4%) and 96 (6%)



Adjusted mean CD4 changes from baseline: 325 cells/mm3 (DTG arm) and 281 cells/mm3 (EFV arm)

SINGLE: Week 96 virologic suppression (<50 copies/mL snapshot)

Walmsley S, et al. CROI 2014; Boston, MA. Abs. 543.

Week 96 adjusted difference in response (95% CI): +8.0% (+2.3% to +13.8%); P=0.006 DTG: 80% EFV: 72% 20 40 60 80 100

Week DTG + ABC/3TC QD EFV/TDF/FTC QD

4 8 12 16 24 32 40 48 60 72 84 96 Proportion of patients, %

3TC, lamivudine; ABC, abacavir; CI, confidence interval; DTG. Dolutegravir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disporoxil fumarate; VF, virologic failure

Dolutegravir vs efavirenz

• At W96, DTG + ABC/3TC was superior to

EFV/FTC/TDF [statistically higher responses; 8% (+2.3%, 13.8%)] which was driven by withdrawals due to AEs in the EFV/FTC/TDF arm (3% vs. 11%)

16

DTG: Treatment-emergent resistance through 48 weeks

 DTG has demonstrated a favourable resistance profile

in several studies to date

SINGLE study (48 weeks), n1 DTG + ABC/3TC OD (N=414) EFV/TDF/FTC OD (N=419) INI resistant mutations NRTI resistant mutations NNRTI resistant mutations 1 (K65K/R) 4 (K101E, K103N, G190G/A)* SPRING-2 study (48 weeks), n2 DTG OD (N=411) RAL BD (N=411) INI resistant mutations 1† NRTI resistant mutations 4†‡ FLAMINGO study (48 weeks), n3 DTG OD (N=242) DRV/r OD (N=245) Treatment-emergent primary mutations (INI, NRTI, PI) *K101E (n=1); K103N (n=1); G190G/A (n=1); K103N + G190G/A (n=1).

†integrase mutations T97T/A, E138E/D, V151V/I and N155H with NRTI mutations A62A/V, K65K/R, K70K/E, AND M184V. ‡M184M/L (n=1); A62A/V (n=1); M184M/V (n=1).

• 1. Walmsley et al. N Engl J Med 2013;369:1807–18 2. Raffi et al. Lancet 2013;381:735–43;
• 3. Clotet et al. Lancet 2014 and supplement [Epub ahead of print]

3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; INI, intergrase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-NNRTI; OD, once-daily; RAL, raltegravir; TDF, tenofovir disoproxil fumarate

Dolutegravir

• In Phase II and III clinical trials, DTG 50 mg QD

has proven to be effective, durable and generally well tolerated in ARV-naïve adult subjects with HIV, without the need for a PK enhancer

• No treatment-emergent mutations leading to drug

resistance have been detected with DTG 50 mg QD in any clinical trial to date in treatment-naïve subjects

• Experienced patients: R → decrease of fitness

Co-morbidities

 Assess CV/ renal. Fragility of bone and DM

early on and before you start ART

 Of course to get VL down is a priority

Co-morbidities

• Aging population: consider type of drugs

Not all PI’s have the same risk and we do not have data for some of them

• Use of statins and risk of DM2: benefit outweighs

risk

• Lipids levels are not the whole story
• The importance of lifestyle changes (weight,

smoking)

Cost: Generic drugs

Drug Patent Expires

TFV 2018 FTC 2016 3TC 2011 EFZ 2013 ATZ 2018 DRV 2016 RIT 2013 RAL 2022

New ARVs

Very exciting!

Rich pipeline of new drugs

 More potent – active on R strains  Less resistance (none?)  When should they be used?  Impact on inflammation

New ART drugs

 Long acting compounds  Advantages and unknowns  Increase bioavaialbiility, help with a dherence

Compartments, decrease toxicity

Strategy: Newer ART Agents (partial list)

NRTI NNRTI PI Entry Inh II

Phase 3 TAF

cenicriviroc

Phase 2 apricitabine

BMS-986001 dexelvucitabine festinavir BILR 355 doravirine (MK-1439) BMS-663068 ibalizumab PF-232798 S/GSK‘744

Phase 1/2

elvucitabine TMC 310911 HGS004

Phase 1 CMX157

RDEA 806 CTP-298 CTP-518 PPL-100 SPI-256 SCH532706 VIR-576 BI 224436 INH-1001

New ART drugs

 TAF  Doravirine MK-1439  Ceniciviroc  BMS-068  GSK-744

NRTI

• Less long-term toxicity
• Active against resistant viral strains

TAF

• Less long-term toxicity
• Active against resistant viral strains

13

Treatment Group N Median DAVG11 [log10 c/mL] P value vs. TDF 300 mg Placebo 7

• 0.01

0.038 TDF 300 mg 6

• 0.48
• TAF 8 mg

9

• 0.76

0.216 TAF 25 mg 8

• 0.94

0.017 TAF 40 mg 8

• 1.08

0.01

Tenofovir Alafenamide Fumarate (TAF): US-120-0104 : 10d monotherapy

Study population: Rx-naïve, VL >2000, CD4 >200 (N=36)

Ruane JAIDS 2013;63:449

17

TAF Phase 3 Program

Study population: Rx-naïve, VL >1000 (2 studies, N=840)

TAF/FTC/EVG/cobi TAF/FTC/EVG/cobi placebo TDF/FTC/EVG/COBI Status: Fully enrolled TDF/FTC/EVG/cobi placebo

NNRTI

• Less toxicity and better tolerability
• Active against resistant viral strains
• Fewer drug interactions

Doravirine (MK-1439)

• Investigational NNRTI
• Pre-clinical

–Potent at low miligram dose –Cytotoxicity and animal toxicity studies negative –Not a CYP450 inhibitor or inducer –Metabolized by CYP3A4 –Active in vitro against viral strains with K103N, Y181C, G190A,

E101K, E138K or K103N/Y181C

• PK: RTV ↑ AUC, Cmin 3X

Lai AAC 2014;58:1652-1663 Anderson ICAAC 2013 #H-1462

Doravirine: Phase 2b Dose Finding

 Study population: Rx-naïve (N=208)  Randomized: TDF/FTC + 4 doses of doravirine vs. EFV  Results:

 VL <40  Toxicity

∆ from EFV: Dizziness (4% vs. 24%) Nightmares (1% vs. 10%)

Morales-Ramirez CROI 2014 #92LB

INSTI

• Once-daily dosing without PK booster
• Active against resistant viral strains

LATTE-1: Oral 744 + RPV

 Phase 2b, partially blinded (to 744 dose)

Margolis CROI 2014 #91LB

N=243

LATTE-1: Results

 LATTE-2: PO 744 + RPV  IM dosing

Margolis CROI 2014 #91LB

CD4 Attachment Inhibitor

• New mechanism of action
• BMS-068

BMS-068: Phase 2b

 Randomized, partially blinded (to 068 dose)  Rx-experienced pts (>1 wk on >1 ART) with

IC50<100nM for 529 (N=251)

 Randomized to TDF + RAL +

 One of 4 doses of 068 [400 mg or 800 mg bid or 600 mg or 1200

mg qd] or ATV/r

 Results:

 8d monotherapy: up to 1.5 log ↓ with 1200 mg qd  Wk 24 VL <50 cps/ml

 068 69-80% vs. ATV/r 75%

 068 no SAE or rx d/c Lalezari CROI 2014 #86

CCR5 Antagonist

needs:

• once-daily dosing

CCR2 Antagonist

• potential anti-inflammatory properties

Cenicriviroc – Phase 3

• 200 mg dose selected
• New formulation
• Phase 3:
• TDF/FTC vs. CVC/3TC [+ a 3rd agent]

Single-tablet regimens under development

Denning and Kalziel Mol Pharm 2013 (epub 9/4/13)

Dual therapies or drug holidays

 Intermittent maintenance therapy: J Leibowitch

ICCARRE

 4 days a week – triple or quadruple therapy  Multitreated  52 y

Gardel trial

• Lopinavir/r - FTC dual versus

Lopinavir/r - 3TC - abacavir triple undetectable

• N=189 patients
• 88.3% in dual vs 83.7% vs triple



Randomized, open-label phase III noninferiority trial



Primary endpoint: HIV-1 RNA < 50 copies/mL (ITT-e, FDA snapshot analysis)

ART-naive patients with HIV-1 RNA > 1000 c/mL; no NRTI/PI resistance; HBsAg negative (N = 426) Lopinavir/Ritonavir 400/100 mg BID + Lamivudine 150 mg BID (n = 217) Lopinavir/Ritonavir 400/100 mg BID + Lamivudine or Emtricitabine + Investigator-selected NRTIs in FDC* (n = 209) Wk 48 primary analysis Stratified by HIV-1 RNA (≤ vs > 100,000 copies/mL) Wk 24 interim analysis

GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs

Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission. *ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%

Dual therapy: PI + INSTI vs triple therapy NEAT 001 – stratification

n = 805 n = 530 n = 275 n = 123 n = 682 Overall < 100,000 copies/mL ≥ 100,000 copies/mL < 200/mm3 ≥ 200/mm3 Baseline HIV-1 RNA Baseline CD4+ 17.4% 7% 36% 39.0% 13.6% 13.7% 7% 27% 21.3% 12.2%

RAL + DRV/r TDF/FTC + DRV/r

10

• 10

20 30 9

Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted p = 0.09* p = 0.02*

• 1.1

8.6

• 3.9

3.5

• 0.05

19.3 4.7 30.8

• 3.4

6.3

Raffi et al. CROI 2014, Abstract 84LB. *Test for homogeneity

• Prof. Nathan CLUMECK

Department of infectious diseases Saint-Pierre University Hospital Brussels, Belgium PI associated with less resistance developement

NNRTI vs PI in Africa

The Lubumbashi Trial

First-line Therapy with LPV/r vs NVP and 2 NRTIs in a Developing Country : 144 Weeks results

Conclusion

 In a resource-limited setting after 144 weeks of follow-up NNRTI-

NRTI first-line regimen is associated with more virologic failure, more drug resistance mutations and a lower immunologic response than a PI-based regimen.

 In Africa there are important gaps in service delivery and program

performance that contribute to :

♦ sub-optimal adherence,

♦ substandard antiretroviral regimen and

♦ acquired drug resistance

 In such settings a boosted-PI strategy could be a better first-

line option. This strategy is recommended in developed countries when baseline genotype analysis is not available

 Cost-effectiveness of such strategy should be evaluated.

cenicriviroc

Eradication

 We have learnt a lot about reservoirs  Virology update and pharmacological aspects-

gene therapy

Eradication: virological reservoirs

Bad news:

 Stable viral reservoir not affected by ART  Reservoir: resting CD4 T cells with their long half-

life, stable

 Can produces replication-competent virus upon

stopping ART

 Establishment of latent reservoir:

Eradication

 Memory precursor CD4+ T cells are cellular

targets for HIV-1 latent infection clearance

 Reactivation and CTL clearance  CTL gag escape variants dominate in CI but not

in PHI

Eradication

 Early ART in PHI: smaller size of latent reservoir

and virus still wild type

 Post-treatment control?  Chronically infected patients: CTLs escape

mutants

 TREAT EARLY!

Eradication-pharmacological approach

 Very early Rx  CD8 CTL  Therapeutic HIV vaccines  Anti-PD-L1 Ab  NK cells: peg INF-alpha and TLR agonists  Bi-specific Ab: neutralsiation: PG9/16-CD4  Immunotoxin cytotoxicity  MAB: Phagocytosis NK-ADCC complement

PG16/19

Eradication

 “Dehydro cortistatin A  HDAC inhibitors, PKC activators  Panobinostat: 100x more potent than vorinostat: 20

mg x 8 weeks FU period for reservoir size

Eradication-panobinostat

1) Induces HIV transcription

• Plasma viremia: NAT screening system
• Increase in HIV transcription to reverse latency

2) Treatment interruption: 9/12 patients

• VL twice weekly
• VL rebound fast in majority, slow in 3
• Trend in decrease in HIV DNA but fast increases

Eradication-panobinostat

Correlation with integrated DNA Suggestion: changes in HIV DNA useful to indicate how long patients can stay off ART

Gene therapy

• Why fails
• Low level of cells transduced

Eradication

j

• ZFN technology
• Cave: Off-target effect/chromosome instability
• TALENs technology: better specificity
• SB-728: safe
• Tre-Recombinase: attacks the reservoir directly. No
• ncology risk

Joachim Hauber, Hamburg

Tre-recombinase

• Tre-recombinase: expand to other subtypes

(LTR)

• Universal: 94% of subtypes A, B and C
• No cytopathic effects in human cells
• Clinical studies to come

Joachim Hauber, Hamburg

Thank you for your attention!