Antiretroviral Therapy:

Drugs, Mechanism of

Action, Adverse Effects

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

University of Florida

Faculty, Florida/Caribbean AIDS Education and Training Center

orricjj@ufl.edu

Disclosure of Financial

Relationships

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 of

interest represented in the presentation.

Timeline of ARV Approvals1987: Zidovudine1987: 1st NRTI Approved

1995: 1st PI

1996: 1st NNRTI

2003: 1st Fusion Inhibitor

The Future: Entry inhibitors, Integrase

inhibitors

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

Nucleoside/Nucleotide Reverse

Transcriptase Inhibitors (NRTI’s)

• 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

HIV Life Cycle

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

Protease inhibitors

(PIs)

NRTIs and NNRTI

Fusion Inhibitors

CCR5 Inhibitors

Non-Nucleoside Reverse

Transcriptase Inhibitors (NNRTIs)

Agent Approved

• Nevirapine (NVP, Viramune) 6/96

• Delavirdine (DLV, Rescriptor) 4/97

• Efavirenz (EFV, Sustiva) 9/98

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

Fusion Inhibitor

• Enfuvirtide (T-20, Fuzeon®)

• Approved March 2003

Enfuvirtide - Fuzeon®

• Unfortunately, Fuzeon® is only active

when injected subcutaneously

• This aspect (in addition to its high cost)

severely limits it use in the correctional

setting

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

Initial Treatment:

Alternative Components

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

lamivudine)

NRTI Options

http://www.aidsetc.org

+

Regimens NOT RecommendedComponents Not Recommended as Part of Regimen

Agent (s) Comment

Stavudine + zidovudine Both thymidine analogs; antagonistic

Stavudine + Didanosine Increased risk of toxicities such as lactic

acidosis and pancreatitis; May be considered

when no other options available and potential

benefits outweigh the risks.

Emtricitabine + lamivudine Similar resistance profiles; no potential

benefit

Regimens NOT RecommendedComponents Not Recommended as Part of Regimen

Agent (s) Comment

Saquinavir (Invirase®),

Darunavir (Prezista®), tipranavir

(Aptivus®)

Should be combined with ritonavir

Efavirenz in pregnancy Teratogenic

Amprenavir oral solution Contraindications due to propylene

glycol content

Amprenavir + fosamprenavir Amprenavir is active component of both

drugs

Atazanavir + indinavir Potential for additive hyperbilirubinemia

Choice of ARVs for Treatment

of the ARV-Naïve Patient

Triple NRTI Regimen-Based Regimens

Only as alternative when PI or NNRTI-based

regimens cannot be used

Alternative • Abacavir + lamivudine +

zidovudine (Available as Trizivir®)

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

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%), consider

separating 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

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

One Pill Once Daly!

• AtriplaTM

(emtricitabine/tenofovir/efavirenz)

– Emtricitabine/tenofovir (Truvada®) +

efavirenz (Sustiva®)

• Approved July 12, 2006

• First collaborative effort between

2 companies to develop

combination pill for HIV treatment

• Not new drugs!

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-1

gp120 and human CCR5 which is necessary

for entry into the cell. Maraviroc does not

prevent HIV-1 entry into CXCR4-tropic or

dual-tropic cells.

www.selzentry.com

HIV Life Cycle

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

Protease inhibitors

(PIs)

NRTIs and NNRTI

Fusion Inhibitors

CCR5 Inhibitors

Maraviroc (SelzentryTM)

• Maraviroc is indicated (in combination with other ARVs) treatment-experienced adult HIV-infected patients

• Maraviroc is not recommended in patients who have dual/mixed tropic or CXCR4-tropic virus

• Use of maraviroc should be based on treatment history and tropism assay results

• The tropism assay is available from Monogram Biosciences, Inc. (For more information go to monogramhiv.com)

www.selzentry.com

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

Concomitant MedicationsMaraviroc

Dose

Other meds including tipranavir/ritonavir, nevirapine, all

NRTIs, 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)

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)

Antiretroviral Agents:

Counseling Points,

Adverse Effects

NRTI’s• 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

NRTI Adverse Effects

Zidovudine Abacavir Lamivudine Emtricitabine

• Bone

marrow

suppression

(anemia/

neutropenia)

• Nausea

• Nail

discoloration

•Hypersensitivity

reaction: fever,

rash, fatigue,

malaise, nausea,

vomiting,

diarrhea, loss of

appetite,

pharyngitis

• Generally well-

tolerated

• Hyperpigmentation

of palms and soles

NRTI Adverse Effects

Stavudine Didanosine Tenofovir

• Peripheral

neuropathy

• Pancreatitis

• Increased

triglycerides

• Pancreatitis

• Peripheral

neuropathy

• Diarrhea

• GI upset

• Flatulence

• Nephrotoxicity

Zidovudine (AZT, Retrovir®)

• Widely held misconceptions among inmates that this was an experimental way to poison HIV+ inmates

• Perception by inmates that many friends/family died from AZT toxicity in the early years of HIV epidemic can result 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 actually people dying of AIDS due to lack of an effective treatment.

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

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

• Headache, muscle aches and insomnia tend to occur more 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 an intravenous (IV) formulation with 10 mg/mL The standard dose 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®)

Patient Case JK

• JK is a 50 year old African American male incarcerated due to repeat drug offenses

• 6 months prior to his incarceration, he found out that he 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 grown children, active drug use including IV heroin and crack/cocaine, drank 12 pack of beer per day on weekend, smokes cigarettes 2 ppd, worked as a painter for 10 years but has been disabled due to back injury

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

Patient Case JK

• What ARV(s) would you include in the

regimen to provide activity against HIV

and HepB?

• What other agents have activity against

HepB?

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 BE

WARRANTED (SEE WARNINGS).

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

NNRTI’s-General Statements

• Hepatic metabolism-no renal dosage adjustments required

• Single mutation confers cross resistance to all available NNRTIs

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

• Many P-450 drug interactions

• Class adverse effects:– increased transaminase levels

– rash (nevirapine > delavirdine > efavirenz)

NNRTI Adverse Effects

• Nevirapine:

– Rash (7%), increased transaminase levels, hepatitis

• Hepatotoxicty more common in women with pretreatment

CD4+ cell counts > 250 cells/mm3 , men with CD4+ cell

counts > 400 cells/mm3 and patients co-infected with

hepatitis B or C

• Monitor LFTs minimally at baseline, 2 weeks, monthly for

the 1st 3 months in all patients

• Efavirenz:

– Rash (1.7%), increased transaminase levels, CNS

side effects (e.g. vivid dreams, dizziness,

drowsiness)

Nevirapine (NVP, Viramune®)

• The most common side effect with Viramune is

skin 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 for

adults, 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

• 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 greater risk)

– Greatest risk during 1st 6 weeks (continued risk through 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®)

• Although there may be no set policy regarding medical hold when starting this medication, it is advisable to consider not starting 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®)

Efavirenz (EFV, Sustiva®)

• Many patients taking efavirenz can

experience nervous system symptoms (for

example, dizziness, vivid dreams,

decreased concentration, and insomnia)

which are generally mild to moderate and

resolve after 2 to 4 weeks.

• Rash is also a potential but uncommon

side effect

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

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

• Some concern that efavirenz can trigger cravings in patients with a history of substance abuse

• Mental health and/or substance abuse supports should be available

• Should be take before bedtime to avoid daytime difficulties

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

Efavirenz (EFV, Sustiva®)

PI’s-General Statements

• Hepatic metabolism-no renal dosage adjustments

• Resistance usually requires multiple mutations

• Many drug interactions

PI’s-General Statements

• Food restrictions– Take all with food EXCEPT:

• Indinavir: take on empty stomach when not combined 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

PI Adverse EffectsAmprenavir/fos-amprenavir

GI intolerance, rash, oral

paresthesias

Atazanavir Hyperbilirubinemia

Indinavir Nephrolithiasis, hyperbilirubinemia

Lopinavir/ritonavir Nausea, diarrhea, pancreatitis

Nelfinavir Diarrhea

RitonavirGI intolerance, paresthesias,

asthenia, taste perversion, hepatitis

Saquinavir GI intolerance

TipranavirGI intolerance, hepatitis, rash,

intracranial hemorrhage

Darunavir GI intolerance, rash

PIs Containing Sulfa Moieties

• Darunavir (Prezista®)

• Fosamprenavir (Lexiva®)

• Tipranavir (Aptivus®)

– Above agents are not contraindicated with sulfa allergy

– History of sulfa allergy did not correlate with rash in studies and patients with history of sulfa allergy were not excluded

– Use with caution

Metabolic Complications

• Glucose intolerance

– Rare diabetes, diabetic ketoacidosis

• Lipodystrophy

– Central obesity, “buffalo hump”, peripheral fat

wasting

• Hyperlipidemia

– Hypertriglyceridemia and/or hypercholesterolemia

• Osteonecrosis, osteopenia, osteoporosis

Lipodystrophy

Dorsocervical fat pad Aka “Buffalo Hump”

Central Obesity

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

Lipoatrophy

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

Facial Wasting

Hendi, et al. Lipodystrophy, HIV. www.emedicine.com

Questions?