Transcript CHAS 2010 HIV Update

Antiretroviral Update
Sarah Ryan, PharmD
February 17, 2010
Learning Objectives
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Adherence counseling
Initiating therapy
Recommended antiretroviral regimens
Antiretrovirals (ARVs) in pregnancy
Common adverse effects of ARVs and
counseling points
• Opportunistic Infection prophylaxis
• Drug Interactions
Adherence
• 95% of ARV doses must be taken for
optimal viral suppression
– QD regimen – missing no more than 1
dose/month
– BID regimen – missing no more than 3
doses/month
• Inadequate viral suppression can lead to
multi-drug and multi-class resistance
Initiating Antiretroviral Therapy
ARVs should be started in all patients with
• History of an AIDS-defining illness
• CD4 < 350
• Pregnancy
• HIV associated nephropathy
• Hepatitis B coinfection when hep B treatment is
indicated
Initiating Antiretroviral
Therapy (cont’d)
• CD4 between 350 and 500
– ARV therapy is recommended
– Panel is divided in its strength of this recommendation
• CD4 > 500
– 50% of panel favors starting therapy
– 50% view treatment as optional
• Patients must be willing to commit to lifelong
treatment (risk vs. benefit, adherence)
Choosing an Initial
Antiretroviral Regimen
3 types of combination regimens
NNRTI + 2 NRTIs
PI (preferably boosted) + 2 NRTIs
INSTI + 2 NRTIs
Regimen selection should be individualized
- Virologic efficacy
- Toxicity
- Pill burden
- Dosing frequency
- Drug-drug interactions
- Resistance testing
- Comorbid conditions
Initial Treatment:
Preferred Regimens
NNRTI - based
- Atripla (efavirenz/tenofovir/emtricitabine)
PI - based
- Boosted Reyataz (atazanavir) + Truvada (tenofovir/emtricitabine)
- Boosted Prezista (darunavir) (once daily) + Truvada
INSTI - based
- Isentress (raltegravir) + Truvada
Pregnancy
- Kaletra (lopinavir/ritonavir) (twice daily) + Combivir
Initial Treatment:
Alternative Regimens
• NNRTI - based
- Sustiva (efavirenz) + Epzicom (lamivudine/abacavir) or
Combivir (zidovudine/lamivudine)
- Viramune (nevirapine) + Combivir
• PI - based
- Boosted Reyataz (atazanavir) + Epzicom or Combivir
- Boosted Lexiva (fosamprenavir) + Truvada
(tenofovir/emtricitabine) or Epzicom or Combivir
- Kaletra (lopinavir/rtv) + Truvada or Epzicom or Combivir
- Boosted Invirase (saquinavir) + Truvada
ARV Regimens
NOT Recommended
• Monotherapy
• Dual-NRTI regimen
• Triple-NRTI Regimen
– Possible exceptions:
• Abacavir/zidovudine/lamivudine (Trizivir)
• Tenofovir (Viread) + zidovudine/lamivudine (Combivir)
ARV Components
NOT Recommended
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Stavudine (Zerit) + Zidovudine (Retrovir)
Stavudine + Didanosine (Videx)
Emtricitabine (Emtriva) + Lamivudine (Epivir)
Saquinavir (Invirase), Darunavir (Prezista), or
Tipranavir (Aptivus) without Ritonavir
• Etravirine (Intellence) + ritonavir boosted Atazanavir
(Reyataz), Fosamprenavir (Lexiva), or Tipranavir
• Etravirine + unboosted PI
Pregnancy
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ARVs decreased transmission from 20-30% to < 2%
1st line: Kaletra (lopinavir/rtv) + combivir (zidovudine/lamivudine)
Most ARVs are Category B or C
Avoid: Sustiva (efavirenz), Category D
Caution
– Viramune (nevirapine) if CD4 > 250
– Videx (didanosone) + Zerit (stavudine)
• Insufficient data
– Prezista (darunavir), Lexiva (fosamprenavir), Aptivus (tipranavir),
Fuzeon (enfuvirtide), Selzentry (maraviroc), Isentress (raltegravir),
Intellence (etravirine)
Adverse Effects and
Counseling Points
NRTIs
• Most are excreted renally
– Dose adjustments are necessary
– Exceptions: zidovudine (Retrovir) and abacavir
(Ziagen)
• Do not have P-450 drug interactions
• Taken without regard to food
– Exception: didanosine (Videx) needs to be taken
on an empty stomach unless taken with
tenofovir (Viread)
Adverse Effects:
NRTIs
• Hypersensitivity reaction – Abacavir (Ziagen)
– 5% of patients, usually within first 6 weeks
– Can be fatal, especially with rechallenge
– S/sx: rash, fever, fatigue, malaise, GI or
respiratory sx
– HLA-B*5701 testing
– Abacavir is a component of Trizivir and Epzicom
Adverse Effects:
NRTIs (cont’d)
• Abacavir (Ziagen, ABC)
– Potential for increased cardiovascular events
• Zidovudine (Retrovir, AZT)
– Bone marrow suppresion
• Tenofovir (Viread, TDF)
– Nephrotoxicity (dose adjust if CrCl<50 ml/min)
• Emtricitabine (Emtriva, FTC)
– Hyperpigmentation of palms and soles
• Didanosine (Videx, ddI)
– Pancreatitis
– Reports of noncirrhotic portal hypertension
Adverse Effects:
NRTIs (cont’d)
Mitochondrial dysfunction
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Lactic acidosis
Peripheral neuropathy
Hepatic steatosis
Lipodystrophy
Pancreatitis
D-drugs
d4T>ddI>ZDV>TDF=ABC=3TC=FTC
(stavudine>didanosine>zidovudine>tenofovir=abacavir=lamivudine=emtricitabine)
Adverse Effects:
Lipodystrophy
• Associated with HIV-infection, PIs, and
NRTIs (especially Zerit, stavudine,d4T)
• Lipodystrophy syndrome:
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Fat accumulation
Insulin resistance
Hyperlipidemia
Fat atrophy
PIs
• Take with food!
– Exceptions: Unboosted indinavir (Crixivan)
should be taken on an empty stomach
– Kaletra (lopinavir/RTV) and Lexiva (fosamprenavir)
can be taken with or without food
– N/V/D are common AEs
– Commonly prescribe antiemetics (promethazine,
compazine, metoclopramide) and antidiarrheals
(loperamide, lomotil, calcium)
Adverse Effects:
PIs
• Atazanvir (Reyataz)
– hyperbilirubinemia
• Indinavir (Crixivan)
– kidney stones
• Nelfinavir (Viracept)
– diarrhea
• Tipranavir (Aptivus)
– intracraneal hemorrhage
• All PIs
– elevated LFTs
• PIs containing sulfa
moieties:
– Darunavir (Prezista)
– Fosamprenavir
(Lexiva)
– Tipranavir (Aptivus)
– Not a contraindication
– Use with caution
Adverse Effects:
NNRTIs
• Nevirapine (Viramune)
– Rash, SJS
• Dose 200mg qd x 14
days, then 200mg bid
– Elevated LFTs, hepatitis,
liver failure
• Higher risk with higher
CD4 counts, in women,
Hep B or C
• LFTs q 2 wks x 1
month, monthly x 3
months, then q 3 months
• Efavirenz (Sustiva)
– CNS AEs: abnormal
dreams, drowsiness,
dizziness, confusion
• Take on an empty
stomach or with a
low-fat snack
– Rash, elevated LFTs,
hyperlipidemia
– Teratogenic
Fusion Inhibitors
• Fuzeon (Enfuvirtide, T-20)
– 90mg BID SQ injection
– Used in treatment experienced patients only
– Injection site reactions are common
CCR5 Inhibitors
• Maraviroc (Selzentry)
– Patients with CCR5 tropic virus
– Recently approved in treatment naïve patients
– Increased risk of CV events, postural
hypotension, hepatotoxicity (can be preceded
by hypersensitivity reaction)
– Common AEs: cough, fever, URI, rash, sore
muscles, abdominal pain, dizziness
– Dosing is based on concomitant meds
Integrase Inhibitors
• Raltegravir (Isentress)
• Now used as part of a first line regimen
• Common AEs: nausea, headache, diarrhea,
fever
• 400mg bid, with or without food
Patient Information
• New Mexico AIDS Education and Training
Center - www.aidsinfonet.org
• Fact sheets on all ARVs as well as topics
such as adherence, resistance, labs, OIs
Opportunistic Infection
Prophylaxis
Howie Ganser, RPh
Preventing OIs:
Pneumocystis carinii (PCP)
• CD4 < 200 or oropharyngeal candidiasis
• 1st choice:
– TMP-SMZ, one DS daily
– TMP-SMZ, one SS daily
• Discontinue when CD4 > 200 for  3
months
Preventing OIs:
PCP (cont’d)
• Alternatives:
– Dapsone 100mg qd
– Dapsone 50mg qd + pyrimethamine 50mg
weekly + leucovorin 25mg weekly
– Dapsone 200mg + pyrimethamine 75mg +
leucovorin 25mg weekly
– Aerosolized pentamidine 300mg monthly
– Atovaquone 1500mg qd
– TMP-SMZ one DS three times weekly
Preventing OIs:
Toxoplasma gondii
• CD4 < 100 and antibody to Toxoplasma
• 1st choice:
– TMP-SMZ, one DS qd
• Discontinue when CD4 > 200 for  3
months
Preventing OIs:
Toxoplasmosis (cont’d)
• Alternative regimens:
– TMP-SMZ, 1 SS daily
– Dapsone 50mg qd + pyrimethamine 50mg
weekly + leucovorin 25mg weekly
– Dapsone 200mg + pyrimethamine 75mg +
leucovorin 25mg weekly
– Atovaquone 1500mg qd with or without
pyrimethamine 25mg qd + leucovorin 10mg qd
Preventing OIs:
Mycobacterium avium complex
• CD4 < 50
• Discontinue when CD4 > 100 for  3 months
• 1st choice:
– Azithromycin 1200mg weekly
– Clarithromycin 500mg bid
• Alternatives:
– Rifabutin 300mg qd
– Azithromycin 1200mg qd + rifabutin 300mg qd
Drug-Drug Interactions
Selected CYP450 Interactions
• Common Inducers
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Nevirapine (Viramune)
Efavirenz (Sustiva)
Rifampin
Rifabutin
Antiepileptics (phenytoin,
CBZ, phenobarb)
– Herbal supplements (St.
John’s Wort, Garlic)
• Common Inhibitors
– Protease Inhibitors
– Ketoconazole >
Itraconazole >
Fluconazole
– Delavirdine (Rescriptor)
– Efavirenz (Sustiva)
– Macrolid abx (erythro >
clarithromycin)
Selected Substrates of CYP450
• CYP 3A4 Substrates
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Benzodiazepines
Macrolides (not azithro)
Quinidine
Cisapride (propulsid)
Sildenafil (Viagra) & other
ED therapies
PIs
Calcium Channel Blockers
Statins
Methadone
• CYP 2D6 Substrates
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Beta blockers
Tricyclic antidepressants
SSRIs
Haloperidol
Risperidone
Protease Inhibitors:
Common Drug Interaction Pearls
• Anxiety/insomnia
– Use lorazepam or temazepam
– Avoid midazolam and triazolam
– Use caution with buspirone and other BZDs
• Lipid lowering drugs
– Use fluvastatin, pravastatin, or rosuvastatin
– Use atorvastatin at low-dose with caution
– Avoid simvastatin and lovastatin
PIs: Common Drug
Interaction Pearls (cont’d)
• Antidepressants
– Start low, and go slow!
– Avoid fluvoxamine, nefazodone, and St. John’s Wort
• Anticonvulsants
– Interactions not likely with valproic acid, gabapentin,
lamotrigine, levetiracetam, topiramate, tiagabine
– Avoid carbamazepine and phenytoin
PIs: Common Drug
Interaction Pearls (cont’d)
• Antipsychotics
– Consider lower starting dose with risperidone,
ziprasidone, aripiprazole, haloperidol
– Avoid chlorpromazine, thioridazine, and
pimozide
– Use caution with quetiapine (may have
increased levels) and olanzapine (may need
higher dose)
PIs: Common Drug
Interaction Pearls (cont’d)
• Erectile Dysfunction
– Start with low doses
– Sildenafil (Viagra) - q 48 hours
– Tadalafil (Cialis) and Vardenafil (Levitra) q 72 hours
Miscellaneous Interactions
• Atazanavir (Reyataz) + Acid-reducing agents
– Give at least 2 hours before or 1 hour after antacids
– Take 2 hours before or 10 hours after H2 blockers (ie:
ranitidine)
– With norvir: Administer simultaneously with and/or ≥ 10
hours after H2 blocker
– With Tenofovir (Viread, Truvada) and H2 blocker in PIexperienced pts, use Reyataz 400mg + Norvir 100mg
– PPIs are not recommended in patients on unboosted Reyataz
or PI- experienced pts
– PI-naïve patients should not exceed omeprazole 20mg qd
administered at least 12 hours prior to boosted Reyataz
Drug Interaction Resources
• www.hivinsite.ucsf.edu
• www.aidsinfo.nih.gov (DHHS Guidelines)
• http://depts.washington.edu/madclin/pharm
acy/drugs/index.html
• Micromedex