1. 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… Early therapyDeferred therapy ProsIncreased viral suppression Improved immune recovery Improved survival Reduced toxic exposure Delaying failure of first regimen Delaying “pill burden” ConsIncreased toxic exposure Increasing drug resistance Increasing “pill burden” Increased virologic failure Incomplete immune recovery Premature death

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

6. 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.

7. 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-tuberculous mycobacterial infection Long-term non-progressor, elite controller

8. 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

9. Principles of therapy - Mechanics

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

11. Brace yourselves…

12. Medication Classes Nucleos(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

13. 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

14. 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

15. Medication Classes Non-nucleoside RTIs Efavirenz (EFV, Sustiva) Nevirapine (NVP, Viramune) Delavirdine (DLV, Rescriptor) Etravirine (ETR, Intelence)

16. 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

17. Medication Classes Protease 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)

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

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

20. 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

21. What HAART to start? “Preferred” regimens EFV/TDF/FTC (Atripla TM ) ATV/rtv (Reyataz TM ) + TDF/FTC (Truvada TM ) DRV/rtv (Prezista TM ) + TDF/FTC (Truvada TM ) RAL (Isentress TM ) + TDF/FTC (Truvada TM ) “Alternative” regimens preferred in pregnancy LPV/rtv (Kaletra TM ) + AZT/3TC (Combivir TM ) NB: this is for ARV-naïve patients

22. Immune reconstitution inflammatory syndromes

23. 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…

24. 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

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

26. 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’

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

28. 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

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