Clinical notes: Management of HAART in patients with HAND

Transcription

1 Clinical notes: Management of HAART in patients with HAND Paola Cinque Dipartment of Infectious Diseases San Raffaele Scientific Institute, Milano, Italy 11 Residential Course on Clinical Pharmacology of Antiretrovirals Turin, January 2016

2 The CNS and ART: features that distinguish CNS from systemic infection Infection of CNS macrophages (macrophage as cell compartment ) Presence of the brain barriers (CNS as anatomical compartment ) Strazielle et al., Rev Med Virol 2005; 15:

3 CNS compartmentalization of HIV infection Without treatment No compartmentalization (neuroasymptomatic) plasma compartmentalization (ADC) Pillai SK et al., Brain 2006

4 Concept of CNS-targeted ART Without treatment No compartmentalization ART effective systemically is also effective intrathecally compartmentalization ART effective systemically is not necessarily also effective intrathecally plasma ARV drugs should be able: 1. To cross the CNS barriers 2. To inhibit HIV replication in CNS macrophages

5 The effect of HIV in the CNS in 2016 (HAND: HIV-associated neurological disorders) In untreated patients HIV-associated dementia Mild neurocognitive/motor impairment In treated patients Neurocognitive impairment viral escape

6 The effect of HIV in the CNS in 2016 (HAND: HIV-associated neurological disorders) In untreated patients HIV-associated dementia Mild neurocognitive/motor impairment May occur in AIDS presenters Is there an indication for a CNS-targeted ART?

7 Log10 HIV-1 RNA copies/ml Different short-term kinetics of virological response in and plasma of ART-treated patients Parallel /plasma response Slower response Plasma Days of HAART Staprans et al., AIDS 1999

8 HIV-1 RNA copy numbers / ml Kinetics of virological response in and plasma in a patient with ADC ART: 3TC+d4T+IDV V WT plasma Months of therapy 15

9 HIV-1 RNA copy numbers / ml Kinetics of virological response in and plasma in a patient with ADC ART: 3TC+d4T+IDV V WT plasma V Months of therapy 15

10 HIV-1 RNA copy numbers / ml Kinetics of virological response in and plasma in a patient with ADC ART: 3TC+d4T+IDV V WT 184V plasma 3 184V Months of therapy 15

11 HIV-1 RNA copy numbers / ml Kinetics of virological response in and plasma in a patient with ADC ART: 3TC+d4T+IDV V WT 184V plasma 3 184V Months of therapy 15

12 Randomized Clinical Trial of Antiretroviral Therapy for Prevention of HAND in naïve pts (Bejing) NVP+AZT+3TC vs. EFV+TDF+3TC 1036 pts, no NCI % M, median CD /µL, median log 4.2 c/ml 8 test battery Scott Letendre et al., CROI 2015

13 NC Function in Africans Failing First-Line ART and Responses to Second Line (EARNEST, Uganda) BL Z-score: PI+2-3 NRTIs vs. PI+RAL vs. PImono 1036 pts 58% F, median CD4 71/µL, >100,000 42% NPZ3 (Trail Making 1-2, Grooved Pegboard) Andrew D. Kambugu, CROI 2015

14 The direct effect of HIV in the CNS (HAND: HIV-associated neurological disorders) In untreated patients HIV-associated dementia Mild neurocognitive/motor impairment Is there an indication for a CNS-targeted ART? May be useful to accelerate clearance in early phase Longer-term effect on NC function not established

15 The direct effect of HIV in the CNS (HAND: HIV-associated neurological disorders) In treated patients Neurocognitive impairment viral escape Is there the indication for a CNS-targeted ART?

16 Prevalence of HAND - Rome, ANI: Asymptomatic Neurocognitive Impairment (NP test abnormalities only) MND: Mild Neurocognitve Disorder (NP test abn + mild functional problems) HAD: HIV-associated dementia 83% suppressed plasma Pennetta, Antinori et al. CROI 2015

17 Potential causes of cognitive deterioration: what mechanisms? HIV (HIV-associated NCI) Previously established irreversible tissue damage by HIV or other causes (legacy effect) Aging Psychiatric disorders Drugs, alcool Alzheimer s and other neurodegenerative diseases Metabolic problems and cerebro-vascular disease Drug toxicity (ART, other drugs)?

18 NCI and ART neuropenetration Cysique et al, Neurology 2009, 73(5):342-8; Tozzi et al, J Acquir Immune Defic Syndr 2009;52:56 63; Smurzynski et al, AIDS 2011;25: ; Marra et al, AIDS 2009, 23(11): ; Winston A, et al. Clin Infect Dis 2010;50: ; Arendt, et al. 18th CROI, Boston (MA, Poster #425; Garvey et al. HIV Clin Trials, 2011;12(6): ; Rourke SB, et al. 6th IAS Conference on HIV Pathogenesis, Teatment and Prevention, Rome, 2011; Ciccarelli N, et al. Antiviral Ther, 2013; Roberston et al. Clin Infect Dis 2012;55(6):868 76; Kahouadji Y, et al. HIV Medicine 2012;14: ; Ellis et al. 20th CROI, Atlanta (GA), 2013; Abst#20. (Courtesy of S. Letendre)

19 The direct effect of HIV in the CNS (HAND: HIV-associated neurological disorders) In treated patients Neurocognitive impairment Is there the indication for a CNS-targeted ART? Effect on NC function not established

20 viral escape >50 c/ml (if plasma suppressed) or > log plasma (if plasma >50) Asymptomatic or symptomatic Ferretti F et al. Curr HIV/AIDS Rep 2015

21 Neuro-symptomatic viral escape (dementia) M, : Progressive dementia History of HIV-D CD4 nadir: : Starts ART Since 2005 TDF,FTC,LPV/r CD4 632 Plasma HIV 265 c/ml HIV 750 c/ml cells 26/µL and plasma mutations to NRTIs (67,75,77,118,184,210,215,219) and PIs (46,54,82,90)

22 Neuro-symptomatic viral escape (dementia) M, : Progressive dementia History of HIV-D CD4 nadir: : Starts ART Since 2005 TDF,FTC,LPV/r CD4 632 Plasma HIV 265 c/ml HIV 750 c/ml cells 26/µL and plasma mutations to NRTIs (67,75,77,118,184,210,215,219) and PIs (46,54,82,90) Resolution by cart optimization for genotypic profile

23 Neuro-symptomatic viral escape (meningoencephalitis) M, : Headache, disarthria, ataxia (days) History of systemic OIs CD4 nadir: : Starts ART (AZT,3TC,LPV/r) Change to TDF,FTC,ATV CD4 290 Plasma HIV 98 c/ml HIV 5200 c/ml cells: 200/µL No mutations to NRTIs and PIs Peluso M et al. AIDS 2012

24 Neuro-symptomatic viral escape (meningoencephalitis) M, : Headache, disarthria, ataxia (days) History of systemic OIs CD4 nadir: : Starts ART (AZT,3TC,LPV/r) Change to TDF,FTC,ATV CD4 290 Plasma HIV 98 c/ml HIV 5200 c/ml cells: 200/µL No mutations to NRTIs and PIs Resolution by cart optimization for neuropenetration Peluso M et al. AIDS 2012

25 Neuro-symptomatic viral escape Can present with NCI and dementia or focal CNS disease Chronic progressive or acute presentation In patients with/out a history of dementia Low nadir CD4 With/out ART resistance

26 Relapse of escape upon ART switch for toxicity or simplification Pt ART at escape 3TC, ABV, FPV/r TDF, FTC, ATV TDF, FTC, FPV/r TDF, FTC, DRV/r (qd) duration (months) * presence of drug resistance mutations Pla 30 < <1 837* Effective ART after escape ABV, FPV/r DRV/r (bid) 3TC, ABV, LPV/r RAL, DRV/r (bid) Pla duration (months) <50 <50 12 <50 <50 42 <50 <50 42 <1 <50 10 ART switch (2nd escape) ABV, FPV/r AZT, ABV, 3TC, DRV/r (qd) 3TC, ABV, LPV/r, TDF, FTC, NVP AZT, RAL, ABV, 3TC, DRV/r (bid) duration (months) Pla 5 < < * 2 <1 853* Effective ART after 2nd escape ABC, FPV/r DRV/r (bid), RAL DRV/r (bid) DRV/r (bid), DTG Pla <50 <50 <50 <50 <50 <50 <1 <50 Ferretti F et al., NeuroHIV Matera 9 October 2015

27 Relapse of escape upon ART switch for toxicity or simplification Pt ART at escape 3TC, ABV, FPV/r TDF, FTC, ATV TDF, FTC, FPV/r TDF, FTC, DRV/r (qd) duration (months) * presence of drug resistance mutations Pla 30 < <1 837* Effective ART after escape ABV, FPV/r DRV/r (bid) 3TC, ABV, LPV/r RAL, DRV/r (bid) Pla duration (months) <50 <50 12 <50 <50 42 <50 <50 42 <1 <50 10 ART switch (2nd escape) ABV, FPV/r AZT, ABV, 3TC, DRV/r (qd) 3TC, ABV, LPV/r, TDF, FTC, NVP AZT, RAL, ABV, 3TC, DRV/r (bid) duration (months) Pla 5 < < * 2 <1 853* Effective ART after 2nd escape ABC, FPV/r DRV/r (bid), RAL DRV/r (bid) DRV/r (bid), DTG Pla <50 <50 <50 <50 <50 <50 <1 <50 Ferretti F et al., NeuroHIV Matera 9 October 2015

28 Relapse of escape upon ART switch for toxicity or simplification Pt ART at escape 3TC, ABV, FPV/r TDF, FTC, ATV TDF, FTC, FPV/r TDF, FTC, DRV/r (qd) duration (months) * presence of drug resistance mutations Pla 30 < <1 837* Effective ART after escape ABV, FPV/r DRV/r (bid) 3TC, ABV, LPV/r RAL, DRV/r (bid) Pla duration (months) <50 n.d. 12 <1 <1 42 <50 n.d 42 <1 <1 10 All responded clinically ART switch (2nd escape) ABV, FPV/r AZT, ABV, 3TC, DRV/r (qd) 3TC, ABV, LPV/r, TDF, FTC, NVP AZT, RAL, ABV, 3TC, DRV/r (bid) duration (months) Pla 5 < < * 2 <1 853* Effective ART after 2nd escape ABC, FPV/r DRV/r (bid), RAL DRV/r (bid) DRV/r (bid), DTG Pla <50 n.d. <50 n.d. <50 n.d <1 <50 All responded clinically Ferretti F et al., NeuroHIV Matera 9 October 2015

29 Possible risk factors in escape Size of brain reservoir Resistance Adherence Efficacy of individual drugs/regimens CNS penetration Efficacy in macrophages/microglial cells

30 The Strategic Timing of Anti-Retroviral Treatment (START) Neurology Substudy: Study Design HIV-infected individuals, ART-naïve, CD4+ count >500 cells/µl, No prior AIDS START Study Randomization N=4658 START participants Neurology Substudy N=608 participants Immediate ART (following randomization) N=297 randomized N=291 with follow-up data Deferred ART CD4+ < 350cells/µL or AIDS N=311 randomized N=301 with follow-up data Planned sample size: N=600, 4 years of follow-up For this analysis, follow-up was censored on May 26, 2015 (unblinding of the START study), mean follow-up 3.3 years. (Price RW et al., EACS Barcelona 2015)

31 Primary Outcome: Change in QNPZ-8 from baseline QNPZ-8 increased in both treatment groups Estimated difference Imm. Def. groups: (95% CI: to 0.03) P=0.63 Statistical Methods: Comparison by intent-to-treat, longitudinal mixed model, adjusted for baseline QNPZ-8 and study visit. (Price RW et al., EACS Barcelona 2015)

32 START Study: Conclusions No overall neurocognitive advantage (or disadvantage) for immediate ART initiation in asymptomatic treatment-naïve individuals with high CD4 counts Suggests: low prevalence of ART-reversible neurocognitive impairment Suggests: low incidence of ART-preventable neurocognitive decline over period of study off treatment No clear evidence of neurotoxicity (Price RW et al., EACS Barcelona 2015)

33 Management of HAART in patients with HAND Conclusions CNS targeted-art is indicated: Untreated patients HIV encephalitis, to accelerate HIV clearance (?) Treated patients viral escape, to suppress ongoing CNS replication

34 Grazie Neurovirology Unit and colleagues at San Raffaele Scientific Institute: Francesca Ferretti, Laura Passeri, Daniele Mennonna, Ester Tuveri, Valentina De Zan e Francesco Campanelli, Simonetta Gerevini, Adriano Lazzarin Collaborators and inspirators: Dick Price (U); Magnus Gisslen and Lars Hagberg (Univ. of Goteborg); Serena Spudich (Yale Univ.) Guidelines companions: Andrea Antinori, Andrea Calcagno (Italian Guidelines); Alan Winston, Renaud De Pasquier (EACS Guidelines) Funding: