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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 (SelzentryTM)
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
Maraviroc (SelzentryTM)
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
Maraviroc (SelzentryTM)
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Maraviroc (SelzentryTM)
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
Nevirapine (NVP, Viramune)
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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.
Nevirapine (NVP, Viramune)
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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
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06
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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
Guidelines for the Use of Antiretroviral Agents in HIV-1 Infected Adults and Adolescents 10/6/06
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
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Questions?