Antiretroviral therapyand immune reconstitution

inflammatory syndromesPatrick Willemot

Core IM Academic ½ day2010 October 14

Overview of presentationHAART

Briefly, when to startPrinciples of therapyMedication classes

Effects, side-effects, and pearlsIRIS

Definitions, clinical presentationsHow to avoidHow to treat

When to start HAART?When the risks of deferring therapy outweigh

the risks of the therapy…

Early therapy Deferred therapyPros Increased viral

suppressionImproved immune recoveryImproved survival

Reduced toxic exposureDelaying failure of first regimenDelaying “pill burden”

Cons Increased toxic exposureIncreasing drug resistanceIncreasing “pill burden”

Increased virologic failureIncomplete immune recoveryPremature death

Risk of progression over 3 yrs

Mellors et al. Annals IM 1997; 126 (12): 946-954.

When to start HAART?Practically speaking:

If symptomatic (incl. OIs, HIVAN, HIVAD, neo)If pregnantIf 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.

When not to defer starting?If unable to adhere to regimen

Psychosocial variablesComorbidities prohibitive to HAART

On meds with signif interactions Unable to ingest/absorb meds Acute non-tuberculous mycobacterial infection

Long-term non-progressor, elite controller

Principles of therapySuppress viral replicationAllow T-cell repopulation

Chances of immunoreconstitution are somewhat predicated upon T-cell nadirVery low nadirs will not repopulate to fully

normal levelsA decimated T-cell library may not have a

immune repertoire upon reconstitution

Principles of therapy - Mechanics

Principles of therapy – in practiceUse NRTI backbone –> 2 NRTIs+ a third active drug from another class

NNRTIritonavir-boosted PIintegrase inhibitor

When failure occurs, use viral genotyping (+/- phenotyping) to guide salvage therapy

Brace yourselves…

Medication ClassesNucleos(t)ide reverse transcriptase inhibitorsLamivudine (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

NRTI coformulations:AZT/3TC (Combivir): bid, more cellular complixTDF/FTC (Truvada): once-daily, potent against

HBV3TC/ABC (Kivexa): once-dailyAZT/3TC/ABC (Trizivir): daily, but virol. inferior

NRTI toxicitiesNRTIs also inhibit γ-polymerase in mitochondria

–> mitochondrial death -> cellular toxicitymyelosuppression, peripheral neuropathy,

lipoatrophy, myopathy, lactic acidosis, steatohepatitis, pancreatitis, (reports of non-cirrhotic portal HTN with ddI)

Abacavir hypersensitivity (5-8%)FLI, progressive ->->-> SIRS deathHLA-B*5701 testing

Tenofovir: A/CKI incl. Fanconi-like

Medication ClassesNon-nucleoside RTIs

Efavirenz (EFV, Sustiva)Nevirapine (NVP, Viramune)Delavirdine (DLV, Rescriptor)

Etravirine (ETR, Intelence)

NNRTI toxicities & issuesToxicities

Rash (including SJS, TEN)Hepatotoxicity (including fulminant hepatic

failure)

Other issues:Efavirenz –> teratogenic, neuropsychiatricNevirapine –> more toxic in women, CD4>250K103N, K181C mutations negate EFV, NVP,

DLV

Coformulation: FTC+TDF+EFV (Atripla): daily dosing

Medication ClassesProtease inhibitorsOld-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)

PI toxicities & issuesGI side effects: NV, DDyslipidemia, LipodystrophyHepatitis

Indinavir -> crystal nephrolithiasisRitonavir -> NVD++, dysgeusiaAtazanavir -> indir hyperbili, nephrolith, needs

H+ for absorption; less dyslip; I50L mutationLPV/rtv –> long QT, TdPDarunavir -> not susceptible to other PI

mutations

Medication ClassesIntegrase strand transfer inhibitorRaltegravir (RAL, Isentress)

ADRs: headache, nausea, diarrhea, fever, CPK elev

lower genetic barrier to resistance than boosted PIs

bid dosing

Medication Classes - OthersCCR5 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

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” regimenspreferred in pregnancy

LPV/rtv (KaletraTM) + AZT/3TC (CombivirTM)

NB: this is for ARV-naïve patients

Immune reconstitution inflammatory syndromes

IRIS… or, when HAART goes awryOIs 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…

IRIS – when to suspect itWhen 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 weeksdon’t necessarily need to have a CD4 rise on

bloodwork

Can develop with most OIsMAC lymphadenitisPulmonary and extrapulmonary TBPneumocystis jiroveci pneumoniaCryptococcosis, endemic mycosesCMV vitritisProgressive multifocal leukoencephalopathyVZV, HSV

Most reactions respond to appropriate antimicrobial tx

IRIS with HBV/HCV is trickiermay evolve to fulminant hepatic failure

Alternatively, may get sAg clearance and sAb positivity

DDx: hepatotoxicity, removal of anti-HBV meds, …

Other immune diseasesSarcoidGraves’

How to avoidIf 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

HAARTCryptococcal meningitis, NTB infectionneed to weigh risk of IRIS with risk of deferring

HAART

Recap of presentationHAART

When to start – when benefits outweigh risksPrinciples of therapy – NRTI backbone +

NNRTI/PI/ISTIMedication classes

Class side-effects, and individual medication issuesIRIS

Concept definitionHow to preventHow to treat

… un chausson avec ça?For lots more info:

www.aidsinfo.nih.gov

Questions?

Comments?

Concerns?