An Update on HIV Therapy

An Update on HIV Therapy: Protease Inhibitors for Treatment Experienced Patients

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An Update on HIV TherapyProtease Inhibitors for Treatment Experienced Patients

Peter A. Kreckel R.Ph

Adjunct Assistant Professor of Pharmacology

Thomas A. Woods, DHSc., M.Ed., PA-C

Associate Professor of Physician Assistant Sciences

This program has been supported by an educational grant

from Boehringer-Ingleheim Inc.

PharmCon is accredited by the Accreditation Council for Pharmacy Education as a provider of

continuing pharmacy education

Speaker: This lecture is being co-presented by two highly qualified professors from St. Francis College of Health Sciences:

Dr. Woods received his Doctor of Health Science in December 2003 from Nova Southeastern University, Fort Lauderdale, Florida, and his BS in Physician Assistant Science from Saint Francis College, Loretto, PA in August 1997. He is currently an Associate Professor,

Department of Physician Assistant Sciences Saint Francis University, where he is the Clinical Medicine HIV/AIDS Unit designer and

instructor. He has earned several teaching awards and has presented numerous presentations as a keynote speaker, in addition to having

authored several publications.

Peter A. Kreckel R.Ph. is a graduate of the University of Pittsburgh, Bachelor of Science in Pharmacy, Magna Cum Laude, Class of 1981. He served as the President of the Pharmacy School Class of 1981 for 3 years, and President of the Pharmacy School Student Counci l for 2

years. During this time he received the Upjohn Achievement Award for leadership and academic achievement. In addition to managing a

retail pharmacy, pharmacist Kreckel is an Adjunct Assistant Professor of Pharmacology, Department of Physicians Assistant Sciences, St.

Francis University. His assignments include teaching a HIV pharmacotherapy course for Physician Assistant students, currently doing their

clinical rotations, that are pursuing a Masters of Medical Science Degree from St. Francis University.

PharmCon is accredited by the accreditation counsel for Pharmacy Education as a provider of continuing pharmacy education

Legal Disclaimer: The material presented here does not necessarily reflect the views of Pharmaceutical

Education Consultants (PharmCon) or the companies that support educational programming. A qualified

healthcare professional should always be consulted before using any therapeutic product discussed. Participants should verify all information and data before treating patients or employing any therapies described

in this educational activity.

This program has been supported by an

educational grant from Boehringer-Ingleheim Inc.

An Update on HIV Therapy

Protease Inhibitors for Treatment Experienced Patients

Accreditation: 798-000-08-087-L02-P

798-000-08-087-L02-T

Target Audience: Pharmacists and Pharmacy Technicians

CE Credits: 1.0 Credit hour or 0.1

CEU for pharmacists/technicians

Expiration Date: 11/25/2011

Program Overview: This program will enhance the pharmacists understanding of HIV therapy and the

use of protease inhibitors for treatment experienced patients. The program includes information on

pharmacologic treatments, patient counseling and a question/answer period.

Objectives:

• Describe the incidence, economic costs, and epidemiology of HIV infection and AIDS in the United States.

•Identify the mechanism of action, efficacy, safety, and tolerability profiles for protease inhibitors and rationale for

prescribing combination therapy when using them.

•Explain the challenges and options with the use of protease inhibitors in treatment experienced HIV patients.

•Outline the pharmacist’s role in counseling and educating HIV patients on drug treatment strategies to improve

the patient’s medication adherence.

This program has been supported by an

educational grant from Boehringer-Ingleheim Inc.

An Update on HIV Therapy

Protease Inhibitors for Treatment Experienced Patients Educational Objectives

1. Describe the incidence, economic costs, and epidemiology of

HIV infection and AIDS in the United States.

2. Identify the mechanism of action, efficacy, safety, and

tolerability profiles for protease inhibitors and rationale for

prescribing combination therapy when using them.

3. Explain the challenges and options with the use of protease

inhibitors in treatment experienced HIV patients.

4. Outline the pharmacist’s role in counseling and educating HIV

patients on drug treatment strategies to improve the patient’s

medication adherence




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HIV/AIDS

Human

Immunodeficiency

Virus

Acquired Immune

Deficiency Syndrome

AIDS

CD4 count below 200

AIDS defining illness (regardless of CD4 count)

A partial list includes …• Pneumocystis carinii pneumonia

• Cytomegalovirus

• Toxoplasmosis of the brain

• Cryptosporidiosis

• Mycobacterium Avium

• Kaposi’s sarcoma

• Candidiasis of the esophagus, trachea, bronchi or lungs

Global estimates for

adults and children, 2007

• People living with HIV

• 33.2 million [30.6 – 36.1 million]

• New HIV infections in 2007

• 2.5 million [1.8 – 4.1 million]

• Deaths due to AIDS in 2007

• 2.1 million [1.9 – 2.4 million]




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Over 6,800 new HIV infections

a day in 2007

• More than 96% are in low and middle income

countries

• About 1,200 are in children under 15 years of age

• About 5,800 are in adults aged 15 years and older

of whom:

• almost 50% are among women

• about 40% are among young people (15-24)

Total: 33.2 (30.6 – 36.1) million

Western & Central Europe

760 000[600 000 – 1.1 million]

Middle East & North Africa

380 000[270 000 – 500 000]Sub-Saharan Africa

22.5 million[20.9 – 24.3 million]

Eastern Europe & Central Asia

1.6 million [1.2 – 2.1 million]

South & South-East Asia

4.0 million[3.3 – 5.1 million]Oceania

75 000[53 000 – 120 000]

North America

1.3 million[480 000 – 1.9 million]

Latin America

1.6 million[1.4 – 1.9 million]

East Asia

800 000[620 000 – 960 000]

Caribbean

230 000[210 000 – 270 000]

Adults and children estimated to

be living with HIV, 2007

A growing

number

of

patients

Cost of HIV/AIDS in the USA

“The Centers for Disease Control and Prevention

(CDC) estimate that about 40,000 people

become infected with HIV every year in the

United States. Under current care standards,

these infections will result in $12.1 billion

annually in future treatment costs.”

(Schackman, Freedberg, Gebo & Moore)




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Costs

• Costs per individual

– Monthly average is $2,100

– Life expectancy increased to 24.2 years

– Lifetime HIV care cost $618,900

• Medication Costs

– more than 70% of cost of treatment




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Race/ethnicity of

persons (including

children) with

HIV/AIDS

diagnosed during

2006




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https://content.nejm.org/content/vol338/issue13/images/large/01f1.jpeg?ck=nck




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HAART Therapy

• Highly Active Antiretroviral

Therapy

• Protease Inhibitors are a

cornerstone of the effective

triple drug HAART therapy

Mortality

CD4 – Track Length

Virus Load – Speed of

Train

HIV




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Therapy Goals

• Increase CD4 cell count

– protect the body’s immune system

– prevent the occurrence of opportunistic

infections

• Decrease viral load count to undetectable

• Maintain quality of life for patient

Compliance with Medications!!!

• Compliance

• Compliance

• Compliance

• Compliance

Compliance issues– 2.6 days changes virus

Adherence and Viral Response

Level of Adherence % pts viral load <400

>95% 81

90-95% 64

80-90% 50

70-80% 25

<70% 6

Adherence and CD4 response

Level of Adherence Mean change inCD4 Count

>95% +60

80-95% +54

<80% -13




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The complicating variables…

• Limited number of medications

• Cost of medications

• Side effects of the medications

• Ability of the virus to mutate: develop resistance to medications

Fusion

FUSION INHIBITOR Prevents binding of HIV virus to

the host cell by blocking a particular domain located on

the gp41 portion of the outer membrane gp120.

Fuzeon ® Enfuviritide T-20 dose 90mg SQ BID 60 = $2,552.74

Entry

CCR5 Co-RECEPTOR ANTAGONIST Binds to CCR5

chemokine co-receptor located on the host cell membrane,

blocking interaction between HIV-1 gp120 and CCR5 needed

for internalization of the virus.

Selzentry® maraviroc 300mg BID(adjust for P450)

$900.00/ month

Overview of Drug Therapy (Reverse transcription inhibitors)

NRTI: Competes with endogenous

deoxynucleotides for the reverse transcriptase.

NRTI prematurely stop DNA elongation. Stops

virus from changing it’s genes from RNA to

DNA.

Drug Therapy: Epivir® (lamivudine) ; Viread®

(tenofovir)

NNRTI: Directly bind reverse transcriptase in a

noncompetitive manner. Stops virus from

changing it’s genes from RNA to DNA.

Drug Therapy: Sustiva® (efavirenz) ; Intelence®

(etravirine)




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Overview of Drug Therapy

HIV INTEGRASE INHIBITOR: Blocking integrase

prevents the integration of HIV-1 DNA into the host’s

genomic sequence. Integrase inhibitors prevent HIV from

taking over the CD4 cell’s command center (nucleus).

Drug Therapy: Insentress® raltegravir

Insentress® raltegravir 400mg BID + or -food

60 = $810.00

Mechanism: reversible inhibitors of HIV aspartyl protease, a viral enzyme responsible for the cleavage of the viral polyprotein into a number of essential enzymes and several structural proteins.

Adverse reactions: Lipodystrophy, hyperglycemia, lipid metabolism, osteonecrosis, osteopenia, osteoporosis, avascular necrosis of the hips.

Protease Inhibitors

Protease Inhibitors

Brand Generic Abbr Dosage COST (AWP) 4/08Viracept® Nelfinavir NFV 1250mg q12 120 = $786.93

Norvir® Ritonavir RTV 100-400mg with other PI for intensification

30 = $321.00

Crixivan® Indinavir IDV 800mg q 8 hrs 180 = $570.96

Agenerase® Amprenavir APV 1200mg q 12hr Withdrawn: 2007Invirase® Saquinavir

(hard gelcap)SQV-HGC

400mg q12 with 400mg Ritonavir

120 = $906.91

Fortovase® Saquinovir (softgel cap)

SQV-SGC

1200mg every 8 hrs Withdrawn: 2005

Reyataz® Atazanavir TAZ 400mg daily 60 = $1,028.55Kaletra® Lopinavir

/RitonavirLPV/r 400mg/100mg BID 60 = $876.98

Aptivus ® Tipranavir 500mg BID give with ritonivir

120 = $1,117.50

Lexiva® fosamprenivir 1.4gm BID 60 = $765.16




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Preferred Protease Inhibitors(for initial PI therapy) Nov 3, 2008

1.Ritonavir-boosted Atazanavir

(REYATAZ®)

2.Ritonavir-boosted Darunavir (Prezista®)

3.Ritonavir-boosted Fosamprenavir

(Lexiva®)

4.Lopinavir/Ritonavir

(co-formulated: twice daily)(Kaletra®)

Ritonavir-boosted Atazanavir

(REYATAZ®)

• Dosage: 400mg every 24 hours with food (unboosted)

• Boosted: 300mg every 24 hours + Ritonavir 100mg every 24 hours

• Advantages: once daily dosing concentrations of Atazanavir are enhanced with Ritonavir boosting Low pill burden (2 daily)

Low risk for PI resistance with failure.

Ritonavir-boosted Atazanavir

(REYATAZ®)

Adverse Effects

• Elevations in LDL, HDL and total cholesterol

• Indirect hyperbilirubinemia (with or without jaundice)

• Nephrolithiasis (causal relationship not yet demonstrated

• Headache, rash GI upset, prolonged PR interval (1st degree AV block)

• Requires acidic environment avoid antacids, H2 receptor antagonists, Proton pump inhibitors. Separate doses from Atazanavir as far as possible.




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Ritonavir-boosted Fosamprenavir

(Lexiva®)

• Dosage: 1400mg (2 x 700mg tablets) twice daily (unboosted)

• Boosted: 1400mg (2x700mg tablets) + Ritonavir 200mg every 24 hours

• Advantages: Twice daily dosing, No food effect

Disadvantages: Skin rashes including Stevens-Johnson syndrome, dyslipidemia, insulin resistance

Lopinavir/Ritonavir (co-formulated)

(Kaletra®)

• Dosage: 400mg + 100mg Ritonavir 2 tablets twice daily– Twice daily dosing

– Preferred PI for pregnant women• (don’t use once daily if pregnant)

– Low risk for PI resistance with failure

– No food restrictions with tablet formulations

• Disadvantages:– GI intolerance especially if using once

daily therapy

– Dyslipidemia and Insulin resistance

– Increase ALT and AST

– Pancreatitis

Prezista® darunavir(Tibotec Labs)

• For treatment-experienced adults, such as those with HIV-1 resistant to more than one Protease Inhibitor (PI)

• No PREZISTA dose adjustment required in patients with mild or moderate hepatic impairment

Prezista® darunavir(Tibotec Labs)

• Ritonavir boosting increases systemic exposure to darunavir by an approximately 14-fold increase

• Therefore, PREZISTA should only be used in combination with 100 mg of ritonavir to achieve sufficient exposures of darunavir




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Ritonavir Boosting

Ritonavir (Norvir®) by Abbott Labs

Most potent inhibitor of the Cytochrome P450 enzyme system

ALL PI are substrates of CYP450-3A4 metabolic rate may be altered in

the presence of CYP inducers or inhibitors

Review of Cytochrome P450Responsible for the metabolism of numerous drugs

Statins (HMGcoAreductase inhibitors)

Simvastatin (Zocor®), Lovastatin (Mevacor), Atorvastatin(Lipitor) are extensively metabolized by P450-3A4

Anti epileptic medications Phenytoin (Dilantin®), Carbamazepine (Tegretol®), Phenobarbital

Antibiotics Erythromycin (E-mycin®), Clarithromycin (Biaxin®) Telithromycin(Ketek®)

Antidepressants Fluoxetine (Prozac®), Sertraline (Zoloft®), Citalopram (Celexa®), Paroxetine (Paxil®)

Methadone

Azole antifungals Ketoconazole (nizoral®), Fluconazole (Diflucan)

Amiodarone (Cordarone®)

Protease Inhibitors

Tests of HIV drug resistance

• Genotypic Assays

– Benefits: cheaper, quicker, may detect the emergence of resistance earlier.

– Draw backs: predictive, not demonstrative

• Phenotypic Assays

– Benefits: Useful in highly HAART-experienced patients needing salvage, may be able to semi-quantitate resistance

– Drawbacks: Long turn-around, expensive

Testing “Genotype”

• Looks at the HIV present in a patients blood and examines it to see what mutations if any exist. – Certain drugs are known for causing certain genetic

mutations.

• If a specific genetic mutation is present, doctors can select which drugs or class of drugs a particular virus may be resistant to.

• Genotypic testing is relatively fast, inexpensive test that is available to most patients.

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Testing “Phenotype”• Virus is exposed it to different concentrations of

HIV medications to determine which drugs are effective.

• Generally used in early stages of drug development long before they are given to humans.

• Phenotypic testing is a slow & expensive. Few patients have access to.

• Currently reserved for patients with multiple drug resistant HIV

When to Start HAART???? Source: Sanford Guide 2008 p.152

HIV

symptoms?

CD4 count Start

Treatment?

Comments

Yes Any Yes

No <200 Yes

No 200-350 Yes* New DHHS

recommendation

No 350< No** Maybe if CD4 decreasing

rapidly or viral load >100,000

copies/ml

NNRTI options

• Preferred: Efavirenz (Sustiva®)

– Dosage: 600mg at bedtime

– Caution: 1st trimester pregnancy

– Caution: unstable psychiatric disease

• Alternative: Nevirapine (Viramune®)

– Dosage: 200mg daily for 14 days; then 200mg BID

Dual NRTI options

• Preferred: Tenofovir + emtricitabine (Truvada®)

– Avoid: in unboosted atazanavir regimens

– Caution: nevirapine (early virologic failure)

– Caution: renal insufficeincy

• Alternative: Abacavir + Lamivudine (Epzicom®)




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To Construct an Antiretroviral Regimen, Select 1

Component from Column A + 1 from Column B (as of Nov 3, 2008)

COLUMN A

(NNRTI or PI options

in alphabetical order)

COLUMN B

(Dual-NRTI options- in

alphabetical order)Preferred

components

NNRTI –efivirenz OR

PI – (Atazanafir +

ritonavir) or

(Darunavir+ritonavir) or

(Fosamprenavir +

ritonavir) or

(Lopinavir+ritonavir)

Preferred

components

Tenofovir/emtricitabine

(co-formulated)

Alternative to

preferred

components

NNRTI –nevirapine OR

PI- atazanavir or

Fosamprenavir or

(Fosamprenavir +

ritonavir) or (Saquinavir

+ ritonavir)

Alternative to

preferred

components

Abacavir/lamivudine (co-

formulated) OR

Didanosine +

(emtricitabine or

lamivudine) OR

Zidovidine/lamivudine

(co-formulated)

IMMUNOLOGIC FAILURE(defined as failure to achieve and maintain adequate CD4

t-cell response in spite of virological suppression)

Defined as suppressed viremia and reached a

CD4 count greater than 500.

• CD4 count less than 200 (42%)

• CD4 200-350 (66%)

• CD4 greater than 350 (85%)

• May expect increase of CD4 count of 150 over

the first year in treatment naïve patients.

• A CD4 t-cell count plateau may occur after 4-6

years of treatment with suppressed viremia.

Goals of HAART

1. Lower viral loads to undetectable levels

2. Elevate CD4 counts

3. Eradication difficult due to:

– latent HIV reservoirs

– poor patient compliance as well as to

mutations with the HIV virus

Successful HAART Therapy

1. Need to have at least two (preferably 3)

active drugs from MULTIPLE drug classes.

2. When maximal suppression is NOT

achieved or LOST changing to a new

regimen with at least two active drugs is

required.

– NEVER change only 1 drug in a failing

regimen.




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Successful HAART Therapy

3. Viral load reduction to below limits of assay

detection in a treatment naïve patient usually

occurs within the first 12 to 24 weeks of

therapy.

4. Predictors of virologic success include:

• High potency of HAART regimen

• Excellent adherence (compliance) to treatment

• Low baseline viremia

• Higher baseline CD4 counts

• Rapid reduction of viremia

Strategies for

Improving Adherence

1. Complex medication regimens

2. Active substance abuse by patients

3. Depression

4. Health system issues

– Interruptions in medications access

– Inadequate education, treatment and support

Pill Box Reminders

• Use of a pillbox increased adherence to

HIV therapy by more than 4%

• Use of pillbox increased the probability of

achieving a viral load of less than 400

copies/ml by 15%

Source: APhA DrugInfoLine (Oct-2007)

The Role of the

Pharmacist

1. Get familiar with the newest treatment

advances of HIV therapy.

2. Work tightly with patients so you can provide

product as well as control inventory.

3. Use of pill reminders.

4. Spend the necessary time with this special

patient population group to encourage

compliance.

Documents

An Update on HIV Therapy