Antiretroviral Update

Sarah Ryan, PharmD

February 17, 2010

Learning Objectives

• 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 regimensNNRTI + 2 NRTIs

PI (preferably boosted) + 2 NRTIsINSTI + 2 NRTIs

Regimen selection should be individualized- Virologic efficacy - Drug-drug interactions- Toxicity - Resistance testing- Pill burden - Comorbid conditions- Dosing frequency

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

• 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

• 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• 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:– 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

Howie Ganser, RPh

Opportunistic InfectionProphylaxis

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– 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– Benzodiazepines– Macrolides (not azithro)– Quinidine– Cisapride (propulsid)– Sildenafil (Viagra) & other ED

therapies– PIs– Calcium Channel Blockers– Statins– Methadone

• CYP 2D6 Substrates– 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 DrugInteraction 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 PI-

experienced 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/pharmacy/drugs/index.html

• Micromedex