Mitä tapahtui HIV-medisiinassa Matti Ristola

Transkriptio

1 Mitä tapahtui HIV-medisiinassa Matti Ristola

2 HIV Cure (HIV:n eradikoiminen isännästä)

3 Ala%esynnytys 35. viikolla HIV- pikates% posi%ivinen synnytyksen yhteydessä Äidin HIV VL 2423 kop/ml, CD4 644 HIV- lääkitys aloiteein 31 tun%a syntymästä Lapsen HIV DNA (30 tun%a) ja HIV RNA (31 tun%a) posi%ivisia Missisippi Baby

4 Missisippi Baby 18 kk: katosi seurannasta ja HIV- lääkitys loppui 23 kk: palasi seurantaan. HIV VL miqaamaqomissa immunologisissa parametreissa ei viiteqä HIV- infek%osta Seuranta jatkuu

5 HIV Cure ja luuydinsiirto Nature / IAS:n kongressi Henrich ja Kuritzkes raportoivat IAS n kongressissa kaksi po%lasta, joiden he arvelevat parantuneen pysyväs% HIV- infek%osta Molemmilla oli ennen lymfoomaan sairastumista tehoava HIV- lääkitys Molemmille teh%in lymfooman hoidon osana luuydinsiirto (luovuqajat eivät olleet CCR5- delta32/delta 32) HIV- lääkitystä jatkeein 8 kuukauqa luuydinsiirron jälkeen Raportoin%hetkellä toinen oli ollut 15 viikkoa ja toinen 7 viikkoa ilman HIV- lääkitystä eikä heillä lääkityksen lopeqamisen jälkeen voitu havaita veressä HI- virusta Hyljintäreak%on arvel%in tuhonneen HI- virukset

6 HIV Cure ja luuydinsiirto Nature / News Henrich ja Kuritzkes, eqä HI- virus oli ilmaantunut molempien po%laiden vereen Remissioiden kesto 32 viikkoa ja 12 viikkoa HIV- lääkityksen lopeqamisesta

7 HIV Cure: Mitä tapahtuu laboratorioissa Luontaiset puolustusmekanismit HIV:ta rajoiqavat tekijät APOBEC- 3G (kohde: Vif) TRIM5α (kohde SIV) Tetherin (BST- 2) (kohde: Vpu) Uusi: SAMHD1 (kohde Vpx) Interferonin indusoima tekijä Uusi: MX2

8 Miten luontaista immuniteeea voisi hyödyntää HIV:n eradikaa%ossa SAMHD1 voi estää HIV:n lisääntymistä lepo%lassa olevissa soluissa MX2 estää HIV:ta infektoimasta isännän soluja

9 HIV-lääkehoidon uudet ohjeet

10 Clinical Impact of New Data From ICAAC, IDWeek, and EACS Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe Recommendation for ART initiation remains at CD4+ cell counts < 350 cells/mm 3 ART can be considered at higher CD4+ counts, depending on patient readiness Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count < > 500 EACS [1] Yes Yes Consider Consider US DHHS [2] Yes Yes Yes Yes IAS-USA [3] Yes Yes Yes Yes WHO [4] Yes Yes Yes Not addressed* *ART may be recommended for the HIV+ partner in serodiscordant couples as prevention of transmission. 1. EACS Guidelines, February DHHS Guidelines, February IAS-USA Guidelines, July WHO ART Guidelines, June 2013.

11 Clinical Impact of New Data From ICAAC, IDWeek, and EACS Update: EACS Guidelines for Treatment of HIV-Infected Pts in Europe Recommended First-Line Agents NRTIs ABC/3TC or TDF/3TC NNRTIs EFV RPV Third Agent Boosted PIs ATV/RTV DRV/RTV INSTIs RAL Changes in initial regimen recommendations in 2013 EACS guidelines: NNRTIs: NVP now alternative rather than preferred Boosted PIs: LPV/RTV now alternative rather than preferred INSTIs: TDF/FTC/EVG/COBI added as alternative regimen EACS Guidelines, October 2013.

12 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 DHHS Guidelines: October 2013 Update on Integrase Inhibitors NNRTI Boosted PI INSTI Preferred Regimens EFV/TDF/FTC ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC DTG + TDF/FTC Alternative Regimens EFV + ABC/3TC RPV/TDF/FTC or RPV + ABC/3TC ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC) RAL + ABC/3TC All 3 integrase inhibitors are now part of preferred first-line regimens DHHS. Guidelines. February DHHS. Recommendation on INSTIs. October 2013.

13 Uusi integraasinestäjä dolutegraviiri

14 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 Dolutegravir Phase III Trials in Treatment- Naive Patients Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 SPRING-2 [1] (active controlled, double blind) SINGLE [2] (active controlled, double blind) FLAMINGO [3] (open label) ART-naive pts VL 1000 c/ml (N = 822) ART-naive pts VL 1000 c/ml HLA-B*5701 neg CrCL > 50 ml/min (N = 833) ART-naive pts VL 1000 c/ml (N = 484) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. 1. Raffi F, et al. Lancet. 2013;381: Walmsley S, et al. ICAAC Abstract H-556b. 3. Feinberg J, et al. ICAAC Abstract H-1464a.

15 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 Patients (%) FLAMINGO: DTG Superior to DRV/RTV + 2 NRTIs in Tx-Naive Patients at Wk 48 Δ +7.1% (95% CI: +0.9% to +13.2%; P =.025) n = Virologic Success* DTG + NRTIs DRV/RTV + NRTIs Virologic Nonresponse Feinberg J, et al. ICAAC Abstract H-1464a No Data *HIV-1 RNA < 50 c/ml as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Treatment-related study d/c: 1% in DTG arm vs 4% in DRV/RTV arm More diarrhea with DRV; more headache with DTG 2 pts (< 1%) in each arm met criteria for VF No pts with resistance in either arm Similar increase in CD4+ cell count at Wk 48: +210 cells/mm 3 in each arm

16 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 FLAMINGO: Subgroup Analysis* at Wk 48 Overall n = BL HIV-1 RNA 100,000 c/ml > 100,000 c/ml Background NRTIs ABC/3TC TDF/FTC BL VL > 100,000 c/ml ABC/3TC at Day 1 TDF/FTC at Day 1 n = 362 n = 122 n = 159 n = 325 n = 25 n = 97 BL CD4+ cell count < 350 cells/mm 3 n = cells/mm 3 n = 313 Sex Female Male Age < 50 yrs 50 yrs Race White Black Favors DRV/RTV Favors DTG HIV-1 RNA < 50 c/ml, % n = 72 n = 412 n = 420 n = 64 n = 349 n = Difference (DTG - DRV/RTV ) *FDA Snapshot analysis. Unadjusted. Clotet B, et al. EACS Abstract LBPS4/6. Reproduced with permission. DTG DRV/RTV

17 HIV/AIDS Update From IAS 2013 SAILING: Dolutegravir vs Raltegravir in ART-Exp d, Integrase Inhibitor Naive Pts Phase III randomized, double-blind, double-dummy, noninferiority study Stratified by number of fully active background agents, use of DRV, screening HIV-1 RNA vs > 50,000 copies/ml Wk 48 Treatment-experienced, integrase inhibitor naive patients with HIV-1 RNA > 400 copies/ml and 2 class resistance (N = 715) Dolutegravir 50 mg QD + Raltegravir placebo + OBR (n = 354) Raltegravir 400 mg BID + Dolutegravir placebo + OBR (n = 361) Cahn P, et al. IAS Abstract WELBB03. Cahn P, et al. Lancet. 2013;382:

18 HIV/AIDS Update From IAS 2013 SAILING: Superior Rate of Virologic Suppression With DTG vs RAL at Wk 48 Subjects (%) Δ 7.4 (95% CI: ; P =.03) DTG + OBR RAL + OBR 9 9 Lower incidence of resistance at VF with DTG vs RAL Integrase resistance: 1% vs 5% OBR resistance: 1% vs 3% Both regimens well tolerated with similar AE profiles Grade 2-4: 8% vs 9% Discontinuations: 3% vs 4% 0 Virologic Success Virologic Nonresponse No Wk 48 Data No difference in outcome between study arms when combined with fully active DRV/RTV Cahn P, et al. IAS Abstract WELBB03. Graphic used with permission.

19 Pitkävaikutteiset HIV-lääkkeet

20 HIV/AIDS Update From IAS 2013 Long-Acting GSK and TMC278 Nanosuspensions: drug nanocrystals suspended in liquid Increased drug dissolution rate Nanocrystal design allows for low injection volume Potential use as long-acting injections for ART regimens, PrEP GSK (DTG analogue) dosed monthly or quarterly TMC278 nanosuspension of RPV dosed monthly Spreen W, et al. IAS Abstract WEAB0103.

21 HIV/AIDS Update From IAS 2013 Coadministration of Long-Acting GSK and TMC278 Randomized, open-label, repeated-dose phase I trial in healthy adults Oral Lead-in* Day 1 Wk 4 Wk 8 Wk 12 Wk 16 Wk 20 Wk 24 Monthly Cohort 1 (n = 10) Cohort 2 (n = 10) Cohort 3 (n = 10) Quarterly Cohort 4 (n = 10) GSK mg IM (LD ) GSK mg IM (LD ) GSK mg IM (LD ) GSK mg IM (LD ) GSK mg SC GSK mg IM GSK mg IM *GSK mg/day for 14 days, then 7-day washout. Loading dose given as split injection dose (2 x 2 ml). Spreen W, et al. IAS Abstract WEAB0103. GSK mg SC GSK mg IM TMC278 (LD ) 1200 mg IM GSK mg IM TMC278 (LD ) 1200 mg IM GSK mg SC GSK mg IM TMC mg IM GSK mg IM TMC mg IM GSK mg IM (LD ) All cohorts followed for 52 wks after last injection (ongoing)

22 HIV/AIDS Update From IAS 2013 Favorable Drug Concentrations With GSK and TMC278 Injections PK results GSK injected every 4 wks or every 12 wks achieved plasma levels > protein-adjusted IC 90 TMC278 dosed every 4 wks achieved plasma levels comparable to those achieved by oral RPV 25 mg/day in HIV-infected patients GSK safe, well tolerated alone and in combination with TMC278 Findings support phase II study of GSK TMC278 as 2-drug ART regimen Spreen W, et al. IAS Abstract WEAB0103.

23 Perustutkimuksen kehittelemiä uusia HIV-lääkkeitä Viruksen proteiinin ja isäntäsolun kofaktorin interak%on estäminen Etuja uusien kohdemolekyylien pipeline lääkeresistenssi ei ehkä kehity helpos% Esteitä proteiini- proteiini interak%ot haasteellisia toksisuus?

24 LEDGIN it in vitro - vaiheessa uusi an%retroviraaliluokka LEDGIN it estävät HIV:n integroitumisen isännän DNA:han eri mekanismilla kuin integraasinestäjät (Kessel ym. JBC 2012) eri kohdemolekyyli kuin nykyisillä integraasinestäjillä (isännän kofaktori LEDG/p75) (Christ ym. Nature 2010) LEDGIN it heikentävät syntyvien HIV- par%kelien infek%ivisyyqä (Jurado ym. PNAS 2013)

25 HCV/HIV koinfektion hoito

26 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 SVR Associated With Lowered Morbidity, Mortality in HIV/HCV Pts With F0-F2 Retrospective analysis of 695 HIV/HCV-coinfected pts with baseline METAVIR F0-F2 scores treated with IFN/RBV between 1/2000-1/2008 in 19 centers in Spain Median follow-up (IQR): No SVR: 59.3 mos ( ) SVR: 59.5 mos ( ) SVR significantly associated with decreased overall mortality and secondary liver outcomes Proportion Free From Event (%) SVR No SVR P = P =.024 Overall mortality Liver-related mortality P = P <.001 Liver decompensation Liver-related events Follow-up (Mos) Berenguer J, et al. ICAAC Abstract H Reproduced with permission.

27 HCV-lääkkeiden kohteita

28 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 C212 Study: Simeprevir + PegIFN/RBV in GT1 HCV/HIV-Coinfected Patients Primary analysis of phase III TMC435-C212 trial (N = 106) 82% white; 82% GT1a HCV; 12% not on ART Of pts on ART, 99% on NRTI, 87% on RAL, 15% on RPV, 3% on MVC, 3% on ENF; boosted PIs and EFV excluded Wk 12 Wk 24 Wk 48 Noncirrhotic pts with GT1 HCV/HIV; HCV tx naive or previous relapser (n = 68) RGT* Simeprevir 150 mg QD + PegIFN/RBV Simeprevir 150 mg QD + PegIFN/RBV PegIFN/RBV PegIFN/RBV Pts with GT1 HCV/HIV and previous partial or null response to HCV tx or cirrhosis (n = 38) Simeprevir 150 mg QD + PegIFN/RBV PegIFN/RBV *Response-guided therapy: Pts with HCV RNA < 25 IU/mL (either detectable or undetectable) at Wk 4 and undetectable HCV RNA at Wk 12 received 24 total wks of therapy; all others received 48 wks. Dieterich D, et al. EACS Abstract LBPS9/5. Reproduced with permission.

29 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 C212 Study: SVR12 With Simeprevir + PegIFN/RBV in Coinfected Patients SVR12 (%) 89% of noncirrhotic pts (54/61) met RGT criteria Safety profile similar to that seen in monoinfected pts Pruritus and photosensitivity in 20% and 2%, respectively Overall (Primary Endpoint) RGT n/n = 0 78/ 106 Overall 42/ 53 Naive* 13/ 15 Relapsers* *Includes only noncirrhotic patients. Dieterich D, et al. EACS Abstract LBPS9/5. Reproduced with permission. 7/ 10 Partial 16/ 28 Null 47/ 54 Overall* 36/ 41 11/ 13 Naive* Relapsers*

30 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 STARTVerso 4: Faldaprevir + PegIFN/RBV in GT1 HCV/HIV-Coinfected Pts Preliminary analysis of phase III STARTVerso 4 trial 83% white/14% black, 79% GT1a HCV, 4% not on ART, 27% on EFV-based ART, 22% on ATV/RTV or DRV/RTV-based ART, 46% on RAL-based ART Randomization or allocation based on ART regimen* Wk 12* Wk 24 Wk 48 Pts coinfected with HIV and GT1 HCV, HCV naive or previous relapser; HIV naive or on stable ART (N = 308) Faldaprevir 240 mg QD + PegIFN/RBV Faldaprevir 120 mg QD + PegIFN/RBV Faldaprevir 240 mg QD + PegIFN/RBV PegIFN/RBV PegIFN/RBV RGT No further tx PegIFN/RBV RGT No further tx *All pts on boosted PIs allocated to 120-mg dose arm. At Wk 12, pts receiving 240 mg QD + P/R were rerandomized 1:1 to continue triple therapy or to P/R to Wk 24. Response-guided therapy: At Wk 24, pts with ETS were rerandomized to continued P/R vs no further treatment; pts without ETS continued P/R to Wk 48. ETS defined as HCV RNA < 25 IU/mL at Wk 4 and HCV RNA < 25 IU/mL, target not detected at Wk 8. Dieterich D, et al. CROI Abstract 40LB. Rockstroh J, et al. EACS Abstract PS9/7.

31 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 SVR4 (%) STARTVerso 4: SVR4 With Faldaprevir + PegIFN/RBV in HCV/HIV-Coinfected Pts n/n = 0 Overall population FDV 120 mg 24 wk FDV 240 mg 12 wk FDV 240 mg 24 wk FDV 240 mg total* / / / / / 185 *Includes additional pts who dropped out before Wk 12. AE profile consistent with HCV-monoinfected pts High SVR rates in both cirrhotic and noncirrhotic pts Cirrhotic: 76% Noncirrhotic: 74% SVR rates by IL28B genotype Rockstroh J, et al. EACS Abstract PS9/7. Reproduced with permission. CC: 89%; CT: 67%; TT: 67%

32 Clinical Impact of New Data From ICAAC, IDWeek, and EACS 2013 Sofosbuvir + PegIFN/RBV in GT1-4 HCV/HIV-Coinfected Patients Single-center, open-label, single-arm trial 92% white; 82% GT1 HCV; 30% on EFV; 22% on ATV/RTV; 26% on RAL; 17% on DRV/RTV; 4% on RPV Noncirrhotic pts, GT1-4 HCV/HIV; HCV-tx naive; on stable ART for > 8 wks; CD4+ cell count > 200 cells/mm 3 (N = 23) Sofosbuvir 400 mg QD + PegIFN/RBV Wk 12 SVR12, % Overall 91 By ART regimen Boosted PI (n = 14) 93 NNRTI (n = 11) 91 RAL (n = 7) 100 Rodriguez-Torres M, et al. IDWeek Abstract 714.