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
Available Antiretrovirals 2014= 25
NRTIs NNRTIs Protease Other Classes STR
Abacavir Efavirenz Inhibitors
Didanosine Nevirapine Atazanavir Fusion Atripla Emtricitabine Etravirine Darunavir inhibitors Eviplera Lamivudine Rilpivirine Fos-Amprenavir • Enfuvirtide Stavudine Indinavir R5 Inhibitors Stribild Tenofovir Lopinavir • Maraviroc Zidovudine Nelfinavir Integrase Ritonavir Inhibitors Saquinavir • Raltegravir Tipranavir • Elvitegravir • Dolutegravir …a potent armamentarium
PI DTG† RPV LPV/r
22 NNRTI
FLAMINGO
19
2
16
4,5
- 15
21 INSTI
STAR
UpECHO to 90% of treatment-naive patients
THRIVE SPRING can now achieve undetectable HIVCASTLE, -1 STARTMRK1 RNAACTG1 -520216 13 ATADAR8
RAL EFV ATV/r DRV/r
10 14
2NN ATV/c** Study Study 103
NVP *EFV/FTC/TDF is not licensed for use in antiretroviral naive patients Large head to head study in Europe17,18 EVG/c ** ATV/c is not yet licensed for use in HIV-infected patients in Europe Small head to head study †DTG is not licensed for use in HIV-infected patients in Europe 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. Toxicities: delayed recognition
Strong Delay Drug / class FDA approval Toxicity signal (years) Zidovudine1 1987 Lipoatrophy 1999 12 Stavudine 1 1994 Lipoatrophy 1999 5 Hepatitis / rash at Nevirapine 1996 2005 9 higher CD4 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 observational 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.
Efficacy: newer treatments outperform EFV Favours EFV Favours Comparator -12% +12%
GS-1021 (STB vs. ATR) N=700 -1.6 3.6 8.8 Week 48: Non-inferiority shown 88% vs. 84% (Snapshot) 0.7 5.1 9.4 GS-102/103/1042 (STB vs. ATR) N=1124 Week 48 (Pooled): Statistically significant 89% vs. 84% (Snapshot) higher VL response
3 -1.1 4.1 9.2 STaR (CPA vs. ATR) N=786 Week 48: Non-inferiority shown 86% vs. 82% (Snapshot) 1.1 13.4 89% vs. 82% (Snapshot) 7.2 Week 48: Statistically significant higher VL BLVL ≤100,000 cpm response -1.9 4.2 10.3 STARTMRK4 (RAL vs. EFV) N=566 Week 48: Non-inferiority shown 86% vs. 82% (ITT, NC=F) 1.7 9.5 17.3 Week 240: Statistically significant 71% vs. 61% (ITT, NC=F) higher VL response SINGLE5 (DTG vs. ATR) N=833 2.5 7.4 12.3 Week 48: Statistically significant superior VL 88% vs. 81% (Snapshot) response ECHO/THRIVE6 (RPV vs. ATR) N=1368 -1.7 2.4 6.6 Week 48: Non-inferiority shown 83% vs. 80% (Snapshot) 1.6 6.6 11.5 90% vs. 84% (TLOVR) Week 48: Statistically significant higher VL response BLVL ≤100,000 cpm -20 -15 -10 -5 0 5 10 15 20 Differences in Percentages (95% CI) Newer ARVs have demonstrated higher rates of virologic suppression compared to EFV-based regimens in HIV-1 infected ART-naïve patients
1. Sax P, et al. Lancet 2012;379:2429–38 4. Rockstroh J, et al. IAC 2012; Washington, DC. LBPE019 2. Ward D, et al. ICAAC 2012; San Francisco, CA. Oral H-555 5. Walmsley S, et al. ICAAC 2012; San Francisco, CA. Oral H-556b 3. Cohen C, et al. HIV-11 2012; Glasgow. O425; Data on File 6. Cohen C, et al. JAIDS 2012;60:33-42 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
Phase III non-inferiority, randomised, double-blind, double-dummy, multicentre study of: SINGLE1 N=833 • 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
Phase IIIb non-inferiority, randomised, active-controlled, multicentre, FLAMINGO2 N=484 open-label study of: • DTG (50 mg QD) + 2 NRTIs • DRV/r (800 mg*/100 mg QD) + 2 NRTIs
Phase III non-inferiority, randomised, double-blind, SPRING-23,4 N=822 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
*Given as 2 x 400 mg tablets NRTI, nucleoside reverse transcriptase inhibitor 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] DRV/r, darunavir/ritonavir; QD, once daily; BID, twice daily; 3. Raffi F et al. Lancet 2013;381:735–43 FDC, fixed-dose combination 4. Raffi F et al. Lancet 2013. doi.org/10.1016/S1473-3099(13)70257-3
SINGLE: Week 96 virologic suppression (<50 copies/mL snapshot)
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%)
DTG + ABC/3TC QD EFV/TDF/FTC QD 100
DTG: 80%
80
EFV: 72% 60 Week 96 adjusted difference in response (95% CI):
40 +8.0% (+2.3% to +13.8%); P=0.006
20
Proportionof % patients, 0 0 4 8 12 16 24 32 40 48 60 72 84 96 Week Adjusted mean CD4 changes from baseline: 325 cells/mm3 (DTG arm) and 281 cells/mm3 (EFV arm)
3TC, lamivudine; ABC, abacavir; CI, confidence interval; DTG. Dolutegravir; EFV, efavirenz; FTC, emtricitabine; TDF, tenofovir disporoxil fumarate; VF, virologic failure Walmsley S, et al. CROI 2014; Boston, MA. Abs. 14543. 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%)
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 0 0 NRTI resistant mutations 0 1 (K65K/R) NNRTI resistant mutations 0 4 (K101E, K103N, G190G/A)* SPRING-2 study (48 weeks), n2 DTG OD (N=411) RAL BD (N=411) INI resistant mutations 0 1† NRTI resistant mutations 0 4†‡ FLAMINGO study (48 weeks), n3 DTG OD (N=242) DRV/r OD (N=245) Treatment-emergent primary mutations (INI, NRTI, PI) 0 0
*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).
3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; INI, intergrase inhibitor; NRTI, nucleoside reverse 1. Walmsley et al. N Engl J Med 2013;369:1807–18 2. Raffi et al. Lancet 2013;381:735–43; transcriptase inhibitor; NNRTI, non-NNRTI; OD, once-daily; RAL, raltegravir; TDF, 3. Clotet et al. Lancet 2014 and supplement [Epub ahead of print] tenofovir disoproxil fumarate 16 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 II Inh Phase 3 TAF cenicriviroc Phase 2 apricitabine BILR 355 BMS-663068 S/GSK‘744 BMS-986001 doravirine ibalizumab dexelvucitabine (MK-1439) PF-232798 festinavir
Phase elvucitabine TMC 310911 HGS004 1/2 Phase 1 CMX157 RDEA 806 CTP-298 SCH532706 BI 224436 CTP-518 VIR-576 INH-1001 PPL-100 SPI-256 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 Tenofovir Alafenamide Fumarate (TAF): US-120-0104 : 10d monotherapy Study population: Rx-naïve, VL >2000, CD4 >200 (N=36) Median Treatment P value vs. N DAVG Group 11 TDF 300 mg [log10 c/mL] 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
13 Ruane JAIDS 2013;63:449 TAF Phase 3 Program
Study population: Rx-naïve, VL >1000 (2 studies, N=840)
TAF/FTC/EVG/cobi TDF/FTC/EVG/cobi placebo Status: Fully enrolled TDF/FTC/EVG/COBI TAF/FTC/EVG/cobi placebo
17 NNRTI
- Less toxicity and better tolerability - Active against resistant viral strains - Fewer drug interactions
Doravirine (MK-1439)
• Investigational NNRTI
Lai AAC 2014;58:1652-1663 • 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 Anderson ICAAC 2013 #H-1462 • PK: RTV ↑ AUC, Cmin 3X
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)
N=243
Margolis CROI 2014 #91LB
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 CCR2 Antagonist needs: • once-daily dosing • potential anti-inflammatory properties
Cenicriviroc – Phase 3 • 200 mg dose selected • New formulation
Denning and Kalziel Mol Pharm 2013 (epub 9/4/13)
• Phase 3: • TDF/FTC vs. CVC/3TC [+ a 3rd agent] Single-tablet regimens under development 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
GARDEL: Dual ART With LPV/RTV + 3TC vs Triple ART With LPV/RTV + 2 NRTIs Randomized, open-label phase III noninferiority trial
Stratified by HIV-1 RNA Wk 24 Wk 48 (≤ vs > 100,000 copies/mL) interim analysis primary analysis
Lopinavir/Ritonavir 400/100 mg BID + Lamivudine 150 mg BID ART-naive patients with HIV-1 (n = 217) RNA > 1000 c/mL; no NRTI/PI resistance; HBsAg negative (N = 426) Lopinavir/Ritonavir 400/100 mg BID + Primary endpoint: HIV-1 RNA < 50 copies/mLLamivudine (ITT-e, orFDA Emtricitabine snapshot + analysis) Investigator-selected NRTIs in FDC* (n = 209)
*ZDV/3TC: 54%; TDF/FTC: 37%; ABC/3TC: 9%
Cahn P, et al. EACS 2013. Abstract LBPS7/6. Reproduced with permission. Dual therapy: PI + INSTI vs triple therapy NEAT 001 – stratification
RAL + TDF/FTC + DRV/r DRV/r Overall n = 805 -1.1 8.6 17.4% 13.7%
Baseline HIV-1 RNA < 100,000 copies/mL n = 530 -3.9 3.5 7% 7% ≥ 100,000 copies/mL n = 275 -0.05 19.3 36% 27% p = 0.09* Baseline CD4+ 4.7 30.8 < 200/mm3 n = 123 39.0% 21.3% ≥ 200/mm3 n = 682 13.6% 12.2% -3.4 6.3 p = 0.02* 9
-10 0 10 20 30 Difference in estimated proportion (95% CI) RAL – TDF/FTC; adjusted *Test for homogeneity Raffi et al. CROI 2014, Abstract 84LB.
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
Prof. Nathan CLUMECK Department of infectious diseases Saint-Pierre University Hospital Brussels, Belgium
PI associated with less resistance developement
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, cenicriviroc ♦ 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. 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
Dr Ole Schmeltz-Sogaardard Aarhus Uni
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 oncology 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!