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Antiretroviral therapy and immune reconstitution inflammatory syndromes

Antiretroviral therapy and immune reconstitution inflammatory syndromes. Patrick Willemot Core IM Academic ½ day 2010 October 14. Overview of presentation. HAART Briefly, when to start Principles of therapy Medication classes Effects, side-effects, and pearls IRIS

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Antiretroviral therapy and immune reconstitution inflammatory syndromes

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  1. Antiretroviral therapyand immune reconstitution inflammatory syndromes Patrick Willemot Core IM Academic ½ day 2010 October 14

  2. Overview of presentation • HAART • Briefly, when to start • Principles of therapy • Medication classes • Effects, side-effects, and pearls • IRIS • Definitions, clinical presentations • How to avoid • How to treat

  3. When to start HAART? • When the risks of deferring therapy outweigh the risks of the therapy…

  4. Risk of progression over 3 yrs Mellors et al. Annals IM 1997; 126 (12): 946-954.

  5. When to start HAART? • Practically speaking: • If symptomatic (incl. OIs, HIVAN, HIVAD, neo) • If pregnant • If HBV coinfected (possibly HCV too…) • If immunologic or virologic progression: • Strong RCT evidence for HAART in pts with CD4 <350 • Observational cohort data for pts with CD4 >350/>500 * • If ready & willing to engage in lifelong, uninterrupted tx * NA-ACCORD. NEJM 2009 Apr 30; 360 (18): 1815-1826.

  6. When not to defer starting? • If unable to adhere to regimen • Psychosocial variables • Comorbidities prohibitive to HAART • On meds with signif interactions • Unable to ingest/absorb meds • Acute non-tuberculousmycobacterial infection • Long-term non-progressor, elite controller

  7. Principles of therapy • Suppress viral replication • Allow T-cell repopulation • Chances of immunoreconstitution are somewhat predicated upon T-cell nadir • Very low nadirs will not repopulate to fully normal levels • A decimated T-cell library may not have a immune repertoire upon reconstitution

  8. Principles of therapy - Mechanics

  9. Principles of therapy – in practice • Use NRTI backbone –> 2 NRTIs • + a third active drug from another class • NNRTI • ritonavir-boosted PI • integraseinhibitor • When failure occurs, use viral genotyping (+/- phenotyping) to guide salvage therapy

  10. Brace yourselves…

  11. Medication ClassesNucleos(t)ide reverse transcriptase inhibitors • Lamivudine (3TC) • Emtricitabine (FTC, Emtriva) • Zidovudine (AZT, ZDV) • Stavudine (d4T, Zerit) • Didanosine (ddI, Videx) • Abacavir (ABC, Ziagen) • Tenofovir (TDF, Viread) - 3TC, FTC select for M184V: less suscept ABC, ddI; more suscept AZT, d4T, TDF - Don’t combine ddI and d4T: high incid neuropathy, pancreatitis, lactic acidosis

  12. NRTI coformulations: • AZT/3TC (Combivir): bid, more cellular complix • TDF/FTC (Truvada): once-daily, potent against HBV • 3TC/ABC (Kivexa): once-daily • AZT/3TC/ABC (Trizivir): daily, but virol. inferior

  13. NRTI toxicities • NRTIs also inhibit γ-polymerase in mitochondria –> mitochondrial death -> cellular toxicity • myelosuppression, peripheral neuropathy, lipoatrophy, myopathy, lactic acidosis, steatohepatitis, pancreatitis, (reports of non-cirrhotic portal HTN with ddI) • Abacavir hypersensitivity (5-8%) • FLI, progressive ->->-> SIRS death • HLA-B*5701 testing • Tenofovir: A/CKI incl. Fanconi-like

  14. Medication ClassesNon-nucleoside RTIs • Efavirenz (EFV, Sustiva) • Nevirapine (NVP, Viramune) • Delavirdine (DLV, Rescriptor) • Etravirine(ETR, Intelence)

  15. NNRTI toxicities & issues • Toxicities • Rash (including SJS, TEN) • Hepatotoxicity (including fulminant hepatic failure) • Other issues: • Efavirenz –> teratogenic, neuropsychiatric • Nevirapine –> more toxic in women, CD4>250 • K103N, K181C mutations negate EFV, NVP, DLV • Coformulation: FTC+TDF+EFV (Atripla): daily dosing

  16. Medication ClassesProtease inhibitors • Old-school: Indinavir, Saquinavir, Nelfinavir, Ritonavir, Tipranavir (more tox, more pills, diff sched) • New school: rtv-boosting (P450 3A4 inh) • Lopinavir/rtv (LPV/rtv, Kaletra) • Fosamprenavir (FPV, Lexiva) • Atazanavir (ATV, Reyataz) • Darunavir (DRV, Prezista)

  17. PI toxicities & issues • GI side effects: NV, D • Dyslipidemia, Lipodystrophy • Hepatitis • Indinavir -> crystal nephrolithiasis • Ritonavir -> NVD++, dysgeusia • Atazanavir -> indirhyperbili, nephrolith, needs H+ for absorption; less dyslip; I50L mutation • LPV/rtv –> long QT, TdP • Darunavir -> not susceptible to other PI mutations

  18. Medication ClassesIntegrase strand transfer inhibitor • Raltegravir (RAL, Isentress) • ADRs: headache, nausea, diarrhea, fever, CPK elev • lower genetic barrier to resistance than boosted PIs • bid dosing

  19. Medication Classes - Others • CCR5 Antagonist (prevents CCR5-gp120 interaction) • Maraviroc (MVC, Celsentri) –> SAP • Coreceptor tropism assay (i.e. look for CXCR4 tropism) • Has durable responses at 96 wks, up and coming • MSK, cough, fever, orthostasis, rash, hepatotox, abdo pain • Fusion inhibitor (binds gp41, prevents memb approx) • Enfuvirtide (T20, Fuzeon) • sc injection bid; site rxn 100%; HSR <1%; pneumonia

  20. What HAART to start? • “Preferred” regimens • EFV/TDF/FTC (AtriplaTM) • ATV/rtv(ReyatazTM) + TDF/FTC (TruvadaTM) • DRV/rtv(PrezistaTM) + TDF/FTC (TruvadaTM) • RAL(IsentressTM) + TDF/FTC (TruvadaTM) • “Alternative” regimens • preferred in pregnancy • LPV/rtv (KaletraTM) + AZT/3TC (CombivirTM) NB: this is for ARV-naïve patients

  21. Immune reconstitution inflammatory syndromes

  22. IRIS… or, when HAART goes awry • OIs regress once specific T-cell immunity is regenerated • The same immunity may precipitate disease as inflammation develops around previously immunoneglected antigens (pathogens or autoantigens) • No formal official definition…

  23. IRIS – when to suspect it • When counts have been below OI thresholds for a long time (months) without adequate prophylaxis • Development within first 4-6 months of initiation of therapy, sometimes within weeks • don’t necessarily need to have a CD4 rise on bloodwork

  24. Can develop with most OIs • MAC lymphadenitis • Pulmonary and extrapulmonary TB • Pneumocystisjiroveci pneumonia • Cryptococcosis, endemic mycoses • CMV vitritis • Progressive multifocal leukoencephalopathy • VZV, HSV • Most reactions respond to appropriate antimicrobial tx

  25. IRIS with HBV/HCV is trickier • may evolve to fulminant hepatic failure • Alternatively, may get sAg clearance and sAb positivity • DDx: hepatotoxicity, removal of anti-HBV meds, … Other immune diseases • Sarcoid • Graves’

  26. How to avoid • If no tx other than HAART (e.g. JC virus -> PML), or evidence for harm from deferring HAART (PCP),thenstart HAART • For OIsfor which there is specific tx, consider OI txprior to HAART (reduce antigen burden) • e.g.: giving PCP prophx 1-2 months before HAART • Cryptococcal meningitis, NTB infection • need to weigh risk of IRIS with risk of deferring HAART

  27. Recap of presentation • HAART • When to start – when benefits outweigh risks • Principles of therapy – NRTI backbone + NNRTI/PI/ISTI • Medication classes • Class side-effects, and individual medication issues • IRIS • Concept definition • How to prevent • How to treat

  28. … un chausson avec ça? • For lots more info: • www.aidsinfo.nih.gov • Questions? • Comments? • Concerns?

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