2 Anti Retro Viral Review Orrick

8/2/2019 2 Anti Retro Viral Review Orrick

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Antiretroviral Therapy:Drugs, Mechanism ofAction, Adverse Effects

Joanne J. Orrick, Pharm.D., BCPSClinical Assistant Professor

University of Florida

Faculty, Florida/Caribbean AIDS Education andTraining [email protected]


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Disclosure of FinancialRelationships

Dr. Orrick has received honoraria from

Boeringer-Ingelheim and Bristol-Myers Squibb

This slide set has been peer-reviewed to ensure that there are no conflicts ofinterest represented in the presentation.


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Timeline of ARV Approvals1987: Zidovudine1987: 1st NRTI Approved

1995: 1st PI

1996: 1st NNRTI

2003: 1st Fusion Inhibitor

The Future: Entry

inhibitors, Integraseinhibitors

1995: Lamivudine, Invirase

1996: Nevirapine, Ritonavir, Indinavir

2003: T-20, Atazanavir, Emtricitabine,Fosamprenavir

2005: Tipranavir

2006: Darunavir

2007: Maraviroc

1991: Didanosine

1992: Zalcitabine

1994: Stavudine

1997: Delavirdine, Nelfinavir, Fortovase

1998: Abacavir, Efavirenz

1999: Amprenavir

2000: Lopinavir/ritonavir

2001: Tenofovir


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Nucleoside/Nucleotide ReverseTranscriptase Inhibitors (NRTIs)

Zidovudine (AZT, ZDV, Retrovir) 3/87 Didanosine (ddI, Videx, Videx EC) 10/91 Stavudine (d4T, Zerit) 6/94

Lamivudine (3TC, Epivir) 11/95

Abacavir (ABC, Ziagen) 12/98 Combivir (AZT/3TC) 9/97 Trizivir (AZT/3TC/ABC) 11/00 Tenofovir (TDF, Viread)* 10/01 Emtricitabine (FTC, Emtriva) 7/03 Epzicom (ABC/3TC) 8/04 Truvada (FTC/TDF) 8/04

Agent Approved

*A nucleotide reverse transcriptase inhibitor


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HIV Life Cycle

From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com

Protease

inhibitors(PIs)

NRTIs andNNRTI

FusionInhibitors

CCR5Inhibitors


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Non-Nucleoside ReverseTranscriptase Inhibitors (NNRTIs)

Agent Approved

Nevirapine (NVP, Viramune) 6/96 Delavirdine (DLV, Rescriptor) 4/97 Efavirenz (EFV, Sustiva) 9/98


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Protease Inhibitors (PIs)

Agent Approved

Saquinavir-HGC (SQV-HGC, Invirase) 12/95 Ritonavir (RTV, Norvir) 3/96 Indinavir (IDV, Crixivan) 3/96 Nelfinavir (NFV, Viracept) 3/97 Saquinavir-SGC (SQV-SGC, Fortovase) 11/97 Amprenavir (APV, Agenerase) 4/99 Lopinavir/ritonavir (KAL, Kaletra) 9/00

Atazanavir (ATV, Reyataz) 6/03

Fosamprenavir (fos-APV, Lexiva) 10/03

Tipranavir (TPV, Aptivus) 6/05

Darunavir (DRV, Prezista) 6/06


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Fusion Inhibitor

Enfuvirtide (T-20, Fuzeon)

Approved March 2003


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Initial Treatment:Preferred Components

*Avoid in pregnant women and women with significant pregnancy potential.**Emtricitabine can be used in place of lamivudine and vice versa.

Efavirenz*

OR

Atazanavir + ritonavir

Fosamprenavir + ritonavir (BID)

Lopinavir/ritonavir (BID)

NNRTI Option

PI Options

Tenofovir +

emtricitabine**OR

Zidovudine +lamivudine**

+

NRTI Options

http://www.aidsetc.org


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Initial Treatment:Alternative Components

*Nevirapine should not be initiated in women with CD4 counts >250 cells/mm3 or men withCD4 counts > 400 cells/mm3

**Atazanavir must be boosted with ritonavir if used in combination with tenofovir

Nevirapine*

OR

Atazanavir**

Fosamprenavir

Fosamprenavir + ritonavir (QD)

Lopinavir/ritonavir (QD)

NNRTI Option

PI Options

Abacavir +lamivudine

Or Didanosine +(emtricitabine orlamivudine)

NRTI Options

http://www.aidsetc.org

+


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Regimens NOT Recommended

Components Not Recommended as Part of Regimen

Agent (s) Comment

Stavudine + zidovudine Both thymidine analogs; antagonistic

Stavudine + Didanosine Increased risk of toxicities such as lacticacidosis and pancreatitis; May be consideredwhen no other options available and potential

benefits outweigh the risks.

Emtricitabine + lamivudine Similar resistance profiles; no potentialbenefit


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Regimens NOT Recommended

Components Not Recommended as Part of RegimenAgent (s) Comment

Saquinavir (Invirase),Darunavir (Prezista), tipranavir

(Aptivus

)

Should be combined with ritonavir

Efavirenz in pregnancy Teratogenic

Amprenavir oral solution Contraindications due to propyleneglycol content

Amprenavir + fosamprenavir Amprenavir is active component of bothdrugs

Atazanavir + indinavir Potential for additive hyperbilirubinemia


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Choice of ARVs for Treatmentof the ARV-Nave Patient

Triple NRTI Regimen-Based Regimens

Only as alternative when PI or NNRTI-basedregimens cannot be used

Alternative Abacavir + lamivudine +zidovudine (Available as Trizivir)


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ARV Update Tipranavir (Aptivus)

Approved June 2005

Darunavir (Prezista) Approved June 2006

Emtricabine/tenofovir/efavirenz (AtriplaTM) Approved August 2006

TMC-125 (Etravirine) Investigational NNRTI-available via expanded access program (EAP)

MK-0518 (Raltegravir) Investigational integrase inhibitor available via EAP

Maraviroc Investigational CCR5 inhibitor available via EAP

Approved August 6th, 2007


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Tipranavir (Aptivus)

Dosage Form 250 mg capsules

Adult Dose 500 mg po bid WITH ritonavir 200 mg po bid

Patient Counseling Points Take with food (high fat meal preferred)

Antacids may decrease TPV/RTV absorption (25-29%), considerseparating dosing

Keep in refrigerator or store at room temperature for up to 60 days

AEs: Hepatotoxicity-monitor LFTs, closely, rash (8-14%) of patients,diarrhea, nausea, vomiting, rare cases of intracranial hemorrhage

Caution with sulfa allergy


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Darunavir (Prezista)

Dosage Form 300 mg capsules

Adult Dose 600 mg po bid WITH ritonavir 100 mg po bid

Patient Counseling Points Take with food

AEs: Rash (7%), abdominal pain, constipation,headache

Caution with sulfa allergy


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One Pill Once Daly!

AtriplaTM

(emtricitabine/tenofovir/efavirenz)

Emtricitabine/tenofovir (Truvada) +

efavirenz (Sustiva)

Approved July 12, 2006

First collaborative effort between

2 companies to developcombination pill for HIV treatment

Not new drugs!


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Maraviroc (SelzentryTM)

First in new class of agents, CCR5 inhibitors

Approved August 6th, 2007

Maraviroc binds to the CCR5 receptor on the

membrane of human cells such as CD4 cells.This binding prevents the interaction of HIV-1gp120 and human CCR5 which is necessaryfor entry into the cell. Maraviroc does notprevent HIV-1 entry into CXCR4-tropic ordual-tropic cells.

www.selzentry.com


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HIV Life Cycle

From The Immunodeficiency Clinic - University Health Network Website, www.tthhivclinic.com

Protease

inhibitors(PIs)

NRTIs andNNRTI

FusionInhibitors

CCR5Inhibitors


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Maraviroc is indicated (in combination withother ARVs) treatment-experienced adultHIV-infected p atients

Maraviroc is not recommended in patients

who have dual/mixed tropic or CXCR4-tropicvirus

Use of maraviroc should be based ontreatment history and tropism assay results

The tropism assay is available fromMonogram Biosciences, Inc. (For moreinformation go to monogramhiv.com)

www.selzentry.com


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Concomitant MedicationsMaraviroc

Dose

CYP3A inhibitors (with or without a CYP3A inducer) Protease inhibitors (except tipranavir/ritonavir)

Delavirdine

Ketoconazole, itraconazole, clarithromycin Other strong CYP3A inhibitors (e.g. telithromycin,

nefazodone)150 mg po bid


www.selzentry.com


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Concomitant MedicationsMaraviroc

Dose

Other meds including tipranavir/ritonavir, nevirapine, allNRTIs, enfuvirtide (T-20)

300 mg po bid

CYP 3A inducers (WITHOUT a strong CYP3A inhibitor) Efavirenz Rifampin Carbamazepine, phenobarbital, phenytoin

600 mg po bid



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Adverse effects/precautions

Hepatotoxicity

may be preceded by a systemic allergic reaction

(pruritic rash, eosinophilia)

Dizziness/postural hypotension

Increased risk of CV events (MI, ischemic

events)


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Antiretroviral Agents:

Counseling Points,Adverse Effects


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NRTIs

Mainly undergo renal excretion EXCEPT Zidovudine (AZT) undergoes glucuronidation

Abacavir metabolized by alcohol dehydrogenase

Do not have P-450 drug interactions

Limited food restrictions Take without regards to meals: zidovudine,

lamivudine, stavudine, tenofovir, emtricitabine

Take on empty stomach: didanosine (except when

given with tenofovir) Class adverse effects

Lactic acidosis with hepatic steatosis


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NRTI Adverse Effects

Zidovudine Abacavir Lamivudine Emtricitabine

Bonemarrowsuppression(anemia/neutropenia)

Nausea

Naildiscoloration

Hypersensitivityreaction: fever,rash, fatigue,malaise, nausea,vomiting,diarrhea, loss ofappetite,pharyngitis

Generally well-tolerated

Hyperpigmentationof palms and soles


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NRTI Adverse Effects

Stavudine Didanosine Tenofovir

Peripheralneuropathy

Pancreatitis

Increased

triglycerides

Pancreatitis Peripheral

neuropathy

Diarrhea

GI upset Flatulence

Nephrotoxicity


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Zidovudine (AZT, Retrovir)

Widely held misconceptions among inmates that this wasan experimental way to poison HIV+ inmates

Perception by inmates that many friends/family diedfrom AZT toxicity in the early years of HIV epidemic canresult in reluctance to take this medication

Correctional provider should point out: AZT was used in much higher does in those years At currently used doses, toxicity is greatly reduced. AZT immunotherapy, while it was the only available treatment at

the time, did not provide an adequate long term response.

The perception that people were dying due to AZT was actuallypeople dying of AIDS due to lack of an effective treatment.

3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005.


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The most common side effects are nausea, headache,muscle aches with muscle tenderness due toinflammation, fever and insomnia

Headache, muscle aches and insomnia tend to occurmore frequently in those patients with advanced HIV

infection Zidovudine comes as a 300 mg tablet, 100 mg capsule,

strawberry-flavored syrup with 50 mg/5mL and as anintravenous (IV) formulation with 10 mg/mL The standarddose for adults is 300 mg every 12 hours, in combination

other anti-HIV therapy

3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, July 2005.

Zidovudine (AZT, Retrovir)


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Patient Case JK

JK is a 50 year old African American maleincarcerated due to repeat drug offenses

6 months prior to his incarceration, he found out thathe had HIV infection but has not yet been treated

He is also known to be co-infected with Hepatitis B and C Medications: none

Social History: Divorced, lived alone, 3 grownchildren, active drug use including IV heroin andcrack/cocaine, drank 12 pack of beer per day onweekend, smokes cigarettes 2 ppd, worked as apainter for 10 years but has been disabled due toback injury


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Patient Case JK

Result: Baseline HIV labs:

CD4: 305 cells/mm3, HIV RNA: 85,650 copies/mL

HIV Genotype: pansensitive

Other Labs: HepBsAg (+), HepBsAb (-), Hep C Ab (+), CMV IgG

(+), Toxo IgG (+)

HepBeAg (+), HBV DNA > 10 million copies/mL

AST 189, ALT 153

All other labs WNL


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Patient Case JK

What ARV(s) would you include in theregimen to provide activity against HIVand HepB?

What other agents have activity againstHepB?


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Black Box Warning

SEVERE ACUTE EXACERBATIONS OF HEPATITIS B HAVE

BEEN REPORTED IN PATIENTS WHO ARE CO-INFECTED

WITH HEPATITIS B VIRUS (HBV) AND HIV AND HAVE

DISCONTINUED _______. HEPATIC FUNCTION SHOULD BE

MONITORED CLOSELY WITH BOTH CLINICAL AND

LABORATORY FOLLOW-UP FOR AT LEAST SEVERAL

MONTHS IN PATIENTS WHO DISCONTINUE _______ AND

ARE CO-INFECTED WITH HIV AND HBV. IF APPROPRIATE,

INITIATION OF ANTI-HEPATITIS B THERAPY MAY BEWARRANTED (SEE WARNINGS).


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Lactic Acidosis with Hepatic Steatosis

Rare complication of NRTI therapy

Signs/Symptoms: Abdominal distention, abdominal pain, nausea,

vomiting, diarrhea, weight loss, difficulty breathing,generalized weakness, myalgias

Risk Factors: Stavudine and didanosine use during pregnancy

Female gender Obesity

Prolonged use of NRTIs


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NNRTIs-General Statements

Hepatic metabolism-no renal dosageadjustments required

Single mutation confers cross resistance toall available NNRTIs

Due to pill burden and lack of potency,delavirdine is rarely used

ManyP-450 drug interactions

Class adverse effects: increased transaminase levels

rash (nevirapine > delavirdine > efavirenz)


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NNRTI Adverse Effects

Nevirapine: Rash (7%), increased transaminase levels, hepatitis

Hepatotoxicty more common in women with pretreatmentCD4+ cell counts > 250 cells/mm3 , men with CD4+ cellcounts > 400 cells/mm3 and patients co-infected withhepatitis B or C

Monitor LFTs minimally at baseline, 2 weeks, monthly forthe 1st 3 months in all patients

Efavirenz:

Rash (1.7%), increased transaminase levels, CNSside effects (e.g. vivid dreams, dizziness,drowsiness)


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Nevirapine (NVP, Viramune)

The most common side effect with Viramune isskin rash that occurs among 17% of patients

The majority of severe rashes from Viramune

occur within the first four weeks of therapy To decrease the rate of rash, a 14 day "lead-in"

dose of one 200 mg tablet daily is used foradults, in combination therapy. The dose can

then be increased to 1 tablet bid (if no rash,hepatitis, or other serious adverse effect)

Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06


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Severe, life-threatening hepatotoxicity

Often associated with rash Greatest risk in women with CD4 >250 (12-fold

greater risk) Increased risk for men with CD4 > 400 (3-fold greaterrisk)

Greatest risk during 1st 6 weeks (continued riskthrough 18 weeks)

Monitor LFTs closely (e.g. baseline, at 2 weeks, 4 weeks,then monthly for first 3 months)

Symptoms: often non-specific, including fatigue,malaise, anorexia, nausea, jaundice

Dear Health Care Professional Letter, Feb 2004 Boehringer Ingelheim



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Although there may be no set policyregarding medical hold when starting thismedication, it is advisable to consider notstarting nevirapine under the following

circumstances*: Immediately prior to an inmate being transferred to

another facility

Immediately prior to release (EOS)

*Unless there is communication with the subsequent medical provider.



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Efavirenz (EFV, Sustiva)

Many patients taking efavirenz canexperience nervous system symptoms (forexample, dizziness, vivid dreams,

decreased concentration, and insomnia)which are generally mild to moderate andresolve after 2 to 4 weeks.

Rash is also a potential but uncommonside effect



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Should be used with caution in patients who have ahistory of psychiatric illness due to side effects includingvivid (sometimes disturbing) dreams, insomnia,somnolence, difficulty concentrating, dizziness, amnesia,confusion or agitation

Some concern that efavirenz can trigger cravings inpatients with a history of substance abuse

Mental health and/or substance abuse supports shouldbe available

Should be take before bedtime to avoid daytimedifficulties


Efavirenz (EFV, Sustiva)


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PIs-General Statements

Hepatic metabolism-no renal dosageadjustments

Resistance usually requires multiple

mutations Many drug interactions


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PIs-General Statements

Food restrictions Take all with food EXCEPT:

Indinavir: take on empty stomach when notcombined with ritonavir

Fosamprenavir: can take with or without food Lopinavir/ritonavir tablets: take with or without food

Class adverse effects Hyperglycemia, lipodystrophy, hyperlipidemia

(less with atazanavir), increased transaminases


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PI Adverse Effects

Amprenavir/fos-amprenavir

GI intolerance, rash, oral

paresthesias

Atazanavir Hyperbilirubinemia

Indinavir Nephrolithiasis, hyperbilirubinemia

Lopinavir/ritonavir

Nausea, diarrhea, pancreatitisNelfinavir Diarrhea

RitonavirGI intolerance, paresthesias,asthenia, taste perversion, hepatitis

Saquinavir GI intolerance

TipranavirGI intolerance, hepatitis, rash,intracranial hemorrhage

Darunavir GI intolerance, rash


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PIs Containing Sulfa Moieties

Darunavir (Prezista)

Fosamprenavir (Lexiva)

Tipranavir (Aptivus)

Above agents are not contraindicated withsulfa allergy

History of sulfa allergy did not correlate withrash in studies and patients with history ofsulfa allergy were not excluded

Use with caution


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Metabolic Complications

Glucose intolerance Rare diabetes, diabetic ketoacidosis

Lipodystrophy

Central obesity, buffalo hump, peripheral fatwasting

Hyperlipidemia

Hypertriglyceridemia and/or hypercholesterolemia

Osteonecrosis, osteopenia, osteoporosis


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Lipodystrophy

Dorsocervical fat pad

Aka Buffalo Hump Central Obesity

Carr and Cooper: New Eng J Med 339, 1296:


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Lipoatrophy

Image courtesy: AIDS Images Library www.aids-images.ch


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Facial Wasting

Hendi, et al. Lipodystrophy, HIV. www.emedicine.com
http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=/websites/emedicine/derm/images/Large/2199der0877-01.jpg&template=izoom2


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Questions?

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