Protezione dalle tossicità d organo nelle strategie terapeutiche drug- sparing

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Massimo Gasparini
8 anni fa
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1 Protezione dalle tossicità d organo nelle strategie terapeutiche drug- sparing Massimo Galli DISC L. Sacco UniMi

2 .tra efficacia e tossicità. Inoltre i dati di tossicità degli studi drug-sparing sono ancora molto limitati

3 Organi: a ciascuna classe il suo. Cuore e vasi: PI boosted>pi>nrti>nnrti Tessuto adiposo: - Perdita: NRTI (timidinici) >NNRTI> PI - Accumulo: PI boosted> PI> altri Fegato: implicate tutte le classi principali Rene: implicati NRTI (TDF) e PI Osso: implicato TDF

4 Pharmacogenetics of adverse effects due to ARV Vidal F et al AIDS Rev 201 0; 1 2:

5 Mitochondrial ageing and antiretroviral therapy exposure Subjects aging 50 years or under were stratified according to cumulative (lifetime) exposure to those NRTIs previously implicated in disruption of mtdna replication. Proportional level of the ageassociated mtdna common deletion (CD) was measured by means of a novel real-time PCR assay.. Amongst all patients CD levels increased with subject age (r=0.467, p=0.005). Mean CD levels were significantly higher in NRTI-exposed than unexposed patients (mean log10(cd/mtdna) ±SEM: NRTI+, ±0.24$;$ NRTI-, -4.62±0.29$;$ p=0.006). Lifetime NRTI exposure was predictive of CD level (r=0.419, p=0.052). Cumulative exposure to certain NRTIs accelerates the accumulation of age-associated mtdna deletion mutations, which appears to be irreversible, and mirrors that expected much later in life due to normal ageing. These data plausibly provide a novel biological mechanism for the phenomenon of accelerated ageing recently described in long-term treated HIV-infected patients. Payne et al Glasgow Abs O234

. Amongst all patients CD levels increased with subject age (r=0.467, p=0.005). Mean CD levels were significantly higher in NRTI-exposed than unexposed patients (mean log10(cd/mtdna) ±SEM: NRTI+, - 3.

6 HAART Hepatotoxicity Drug Mechanism Manifestation NRTI AZT d4t ddi ddc Protease Inhibitors NNRTI Impaired mitochondrial polymerase gamma function? Inhibition of retinoic acid binding protein UDP-glucuronyl transferase competition? Impaired mitochondrial polymerase gamma? Immune-mediated hypersensitivity Lactic Acidosis Steatosis Hepatocellular injury Steatosis Unconjugated hyperbilirubinemia Lactic Acidosis Steatosis Eosinophilic injury

Inhibition of retinoic acid binding protein UDP-glucuronyl transferase competition?

7 Nuovi scenari: alla ricerca di compagni di strada per la terapia anti-hcv Pur con differenze tra i diversi centri, la maggioranza dei coinfetti da HCV in terapia antiretrovirale non hanno ricevuto, soprattutto se portatori di sottotipi difficili, alcun trattamento anti-hcv o hanno sperimentato fallimenti terapeutici Gli scenari aperti dalla disponibilità di nuovi farmaci anti-hcv richiedono l identificazione di combinazioni terapeutiche che consentano la prosecuzione della terapia antiretrovirale contemporaneamente al trattamento di HCV Le possibili interazioni tra i nuovi anti-hcv e gli ARV sono ancora tutte da esplorare, ma è verosimile che accanto alla ricerca di combinazioni genericamente liver friendly l identificazione di combinazioni permissive acquisisca una notevole importanza nel prossimo futuro.

identificazione di combinazioni terapeutiche che consentano la prosecuzione della terapia antiretrovirale contemporaneamente al trattamento di HCV Le possibili interazioni tra i nuovi anti-hcv e gli

8 HIV Clin Trials 2006; 7(6): HIV Clin Trials 2008; 9(5):

10 Cumulative exposure to ART and risk of CKD: adjusted IRRs (per year of exposure) Tenofovir Indinavir Cockroft-Gault MDRD CKD-EPI INSIGHT def Censoring ATV Censoring TDF Censoring PI/r Atazanavir Lopinavir Adapted from Kirk et al. 1 7th CROI, San Francisco, CA, 201 0, abs 1 07LB

Censoring ATV Censoring TDF Censoring PI/r Atazanavir Lopinavir 0.9 1.

12 Impact of TDF on renal function in ARV-naïve patients Retrospective cohort analysis, Kaiser Permanente cohort. Change of GFR from baseline by TDF exposure and baseline GFR Horberg et al JAIDS 201 0; 53: 62-69

13 Changes in individual egfr values after TDF cessation JAIDS 201 0; 55: 78-81

14 Smoking, female gender and PI use are associated with decreasing renal function in TDF-containing HAART Variable CG p-value MDRD p-value CK-EPI p-value Increasing decrease decrease decrease age Increasing increase < NA ns decrease BMI PI/r usage NA ns decrease decrease Smoking decrease decrease decrease 0.05 Female sex decrease decrease decrease OSMA study group, Glasgow [P084]

0006 age Increasing increase < 0.0001 NA ns decrease 0.059 BMI PI/r usage NA ns decrease 0.072 decrease 0.

15 Vitamin D and clinical disease progression in HIV infection: Results from the EuroSIDA study Viard et al Glasgow Abs O patients randomly selected after stratification by region. 25(OH)D levels were measured in a single laboratory from stored plasma samples. 36% percent of patients had 25(OH) <12 ng/ml, 31.3% between 12.1 and 20 ng/ml, and 32.7% > 20 ng/ml. Older persons, patients of Black ethnic origin, living outside Southern Europe and Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher risk of having low 25(OH)D levels, while patients receiving protease inhibitors were at a lower risk. Compared to those in the lowest 25(OH)D tertile, those in the medium and high tertiles had a significantly lower risk of clinical progression.

Older persons, patients of Black ethnic origin, living outside Southern Europe and Argentina, sampled during winter, and infected with HIV through nonhomosexual exposure were at higher risk of having

16 Tenofovir use is associated with low vitamin D levels in a Spanish HIV cohort Cross-sectional study of 94 adult HIV outpatients, median age 44 years (IQR 40 to 48); 69.1% males, 93,6% whites. Mean CD4+ cell count 446 cells/μl (IQR 312 to 586). Viral load <50 copies/ml in 78.7%. Median 25(OH)D level was 17.7 μg/l (IQR 11.9 TO 24.3): in 87.2% <30 μg/l (suboptimal), in 57.4% <20 μg/l (deficient) and in 19.1% <10 μg/l (severely deficient). Factors associated with low levels of 25(OH)D were heterosexual vs. IVDU (OR 13.3, 95% CI , p=0.003), season (spring vs. summer; OR 16.8, 95% CI , p=0.0001), age >45 vs < 45 years (OR 10.5, 95% CI %, p=0.002), CD4+ cells nadir <200 vs >200 cells/μl (OR 4.1, 95% CI , p=0.049), and tenofovir vs. abacavir therapy (OR 12.7, 95% CI , p=0.01). Further studies on causality of this association and the need of control bone-mineral density in tenofovir-treated patients seems warranted. Cervero et al Glaqsgow Abs 1 04

4% <20 μg/l (deficient) and in 19.1% <10 μg/l (severely deficient). Factors associated with low levels of 25(OH)D were heterosexual vs. IVDU (OR 13.3, 95% CI 2.4-74.1, p=0.003), season (spring vs.

17 ACTG 5142:Mean Percent Change from Baseline in BMD Observed Changes (irrespective of treatment changes) % Change in BMD from Baseline NRTI Spare LPV EFV EFV/ TDF LPV/ TDF Huang et al 201 0

19 Osservazioni finali L invecchiamento progressivo della popolazione dei pazienti in trattamento e caratteristiche individuali che comportano rischi maggiori di tossicità impongono l individuazione di strategie alternative all attuale gold standard terapeutico Le strategie NRTI-sparing rappresentano un possibile percorso alternativo nelle situazioni in cui le tossicità d organo associate a questa classe non possano essere tollerate L impiego di tali strategie in caso di necessità non implica che se ne sia obbligatoriamente dimostrata la non inferiorità rispetto al gold standard, ma implica l adozione di procedure di controllo adeguate L eventuale impatto delle strategie NRTI-sparing nel ridurre il rischio cardiovascolare e le alterazioni del tessuto adiposo merita tuttavia una più completa definizione L uso di nuovi farmaci anti-hcv in pazienti in ART contribuirà probabilmente a rivoluzionare i criteri d impiego degli ARV nei coinfetti, con possibili ricadute anche sugli altri

classe non possano essere tollerate L impiego di tali strategie in caso di necessità non implica che se ne sia obbligatoriamente dimostrata la non inferiorità rispetto al gold standard, ma implica l

20 Grazie per l attenzione

21 ACTG 5224s A5224s (n=269) Bone Fractures 5.6% had 1 fracture (all traumatic) No statistically significant differences between NRTI components or NNRTI/PI components in fracture rate (Fisher s exact) or time to first fracture (log-rank test) A5202 (n=1857) 4.3% fracture rate (12.7% of those atraumatic) No statistically significant differences between NRTI components or NNRTI/PI components in fracture rate (Fisher s exact), incidence or time to first fracture (log-rank test) TDF/FTC + EFV (n=464) TDF/FTC + ATV/r (n=465) ABC/3TC+ EFV (n=465) ABC/3TC+ ATV/r (n=463) Total (n=1857) % with 1 fractures 4.5% 4.5% 4.7% 3.4% 4.3% Incidence per 100 pt-year McComsey. et al. 1 7th CROI, San Francisco, CA, 201 0, presentation 1 06LB

22 ACTG 5224s Mean (95% CI) Percent Change in Lumbar Spine BMD (ITT) * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.63)

23 ACTG 5224s Mean (95% CI) Percent Change Hip BMD (ITT) * * * -linear regression No significant interaction of NRTI and NNRTI/PI components (p=0.69)

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