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GIANE PAULA P. RUIZ MAIN PHARMACY

THE WORLDS FAVOURITE NEWSPAPER
- Since 2000

AN UPDATE ON THE CURRENT TREATMENT OF HIV

GOAL
To familiarize Phs with the current treatment options for HIV, the antiretrovirals and the appropriate monitoring parameters of therapy.

OBJECTIVES
KNOW UNDERSTAND RECOGNIZE MONITOR

What is HIV/AIDS?
HIV is an acronym for Human Immunodeficiency Virus HIV is the known cause of AIDS, which is an acronym for Acquired Immune Deficiency Syndrome HIV attacks the bodys immune system by destroying essential cells that help the body fight and destroy invading germs

How HIV/AIDS is spread

Direct blood to blood contact with an infected person Sharing of drug needles Sexual contact Pregnancy and after-birth fluids Tainted blood transfusions

Who has HIV/AIDS?

Fastest growing population in the US is young, heterosexual, African-American women aged 18-35 Contracting the virus from unfaithful partners living on the down-lo (homosexual or bisexual men who front as heterosexuals and live active homosexual or bisexual lives in secret)

Africa is the continent most damaged by HIV/AIDS India is the nation where HIV/AIDS is growing the fastest

How to tell if one has HIV/AIDS

HIV/AIDS is determined by a blood test administered by a doctor There are many symptoms but HIV/AIDS is not diagnosed symptomatically If you suspect you have been infected with HIV/AIDS, consult your doctor or local health clinic for an HIV test

Antiretroviral Classes
NRTIs (Nucleoside OR Nucleotide Reverse Transcriptase Inhibitors, aka Nukes) NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors, aka Non-Nukes)

PIs (Protease Inhibitors)

Fusion Inhibitors Chemokine Receptor

Antagonists Integrase Inhibitors

Mechanism of Action of ARVs

Integrase Inhibitor Protease Inhibitor

Fusion Inhibitor & Chemokine Receptor Antagonist

NNRTI
NRTI
Illustration by David Klemm

Antiretroviral Drug Approval: Maraviroc Raltegravir 1987 - 2007 FPV DRV

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EFV TDF LPV/r ABC NFV APV DLV FTC ATV TPV T-20

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RTV IDV NVP 3TC SQV d4T AZT ddI ddC

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0
1987 1991 1993 1995 1997 1999 2001 2003 2006

NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR

NRTIs
Drug Standard Dose* Dosage forms Common Side Effects Fatigue, malaise, HA myalgia, anemia, GI Well tolerated Metabolism/ Elimination Renal

Zidovudine (ZDV/AZT) Retrovir Lamivudine (3TC) Epivir Emtricitabine (FTC) Emtriva Didanosine (ddI) Videx

300mg bid*

300mg tab, 100mg cap, iv, oral soln 150, 300mg tab, oral soln

150mg bid* or 300mg qd

Renal

200mg qd*

200mg cap

Well tolerated

Renal

400mg EC qd ( 60kg) 250mg EC qd (<60kg)*

125,200,250, 400mg cap, pwdr for soln

Pancreatitis, peripheral neuropathy, LA/HS

Renal

Note: Lactic acidosis can occur with any NRTIs

*dose reduce for renal dysfunction

NRTIs
Drug Stavudine (d4T) Zerit IR Standard Dose* 40mg bid ( 60kg) 30mg bid (<60kg) * Dosage forms 15,20,30,40 mg cap,oral soln Common Side Effects Peripheral neuropathy, Pancreatitis, LA/HS, Lipoatrophy, facial wasting hypersensitivity Metabolism/ Elimination Renal

Abacavir (ABC) Ziagen

300mg bid, 600mg qd

300mg tabs, oral soln

Hepatic by alcohol dehydrogenase and glucuronyl transferase Renal

Tenofovir (TDF) Viread

300mg qd*

300mg tabs

Few SEs, renal toxicity

*dose reduce for renal dysfunction

NRTI Combinations
Drug Lamivudine/ Zidovudine (COM) Combivir Abacavir/Lamivudine/Zidovudine (TZV) Trizivir Tenofovir/Emtricitabine Truvada Abacavir/Lamivudine Epzicom Tenofovir/Emtricitabine/Efavirenz Atripla Standard Dose* 1 Tablet bid * Dosage forms 150/300mg tabs 300/150/300mg tabs 300/200mg tabs 600/300mg tabs 300/200/600 mg tabs

1 Tablet bid* 1 Tablet qd* 1 Tablet qd* 1 Tablet qd*

*dose reduce for renal dysfunction

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR

NNRTIs
Drug
Delavirdine (DLV) Rescriptor Nevirapine (NVP) Viramune

Standard Dose
400 mg tid

Dosage forms
100mg tab, 200mg cap 200mg tabs, Oral susp 50, 100, 200mg cap, 600mg tab

Common AEs
Rash

Metabolism
Potent CYP3A inhibitor; 3A4 substrate CYP3A inducer, auto inducer; 3A4, 2B6 substrate CYP3A, 2B6 inducer; 2B6, 3A4 substrate

200 mg qd x 14 d then 200 mg bid

Rash (SJ), hepatotoxicity Vivid dreams, drowsiness or insomnia, rash (SJ), hyperlipidemia

Efavirenz* 600 mg qhs (EFV) Sustiva

*Pregnancy Class D

PROTEASE INHIBITORS

Protease Inhibitors
Standard Dose Dosage Forms Metabolism Common AEs**

Saquinavir (Invirase) (1)

1000/ rtv 100 bid or 1600/ rtv 100 qd

200mg caps, 500mg tabs

3A, Pgp substrate; weak 3A inhibitor 2C19 (M83A) substrate; weak 3A inhibitor 3A, Pgp substrate; 3A inhibitor; 2C9, 2C19 inducer 3A, Pgp substrate; weak 3A inhibitor

GI intolerance

Nelfinavir (Viracept) (1)

1250 bid, 750mg tid

250mg, 625mg tabs, 50mg/g oral pwdr

Diarrhea

Lopinavir/ 400/100 bid ritonavir (Kaletra) (1,2) Indinavir 800/ rtv 100 bid, (Crixivan) 800mg tid (1-when taken with rtv)

200/50 mg tabs, 80/20mg/5mL soln

Dyspepsia, Nausea, vomiting, diarrhea, flatulence Nephrolithiasis Drink 7-8 glasses of water per day; hyperbilirubinemia

100, 200, 333, 400mg caps

(1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance

Protease Inhibitors
Standard Dose Dosage Forms Metabolism Common AEs**

Atazanavir (Reyataz) (1)

400qd or 300/ rtv 100qd

100, 150, 200mg caps

3A substrate; 3A and UGT1A1 inhibitor 3A4, Pgp substrate; 3A4 inducer/ Inhibitor 3A4, Pgp substrate; 3A4, inducer/ inhibitor??; Pgp inducer 3A4 substrate; 3A4 inhibitors 2D6, 3A4, Pgp substrate; 3A4, Pgp inhibitor

Hyperbilirubinemia, PR prolongation

Fosamprenavir (Lexiva) (1)

1400mg bid; 700/100 RTV mg bid; 1400/200 RTV mg qd 500/200 RTV mg bid

700mg tabs (Agenerase-APV liq available) 250mg caps

Rash, GI intolerance, caution with sulfur allergy Hepatotoxicity, Increased bleeding caution with sulfur allergy Diarrhea, nausea, HA, nasopharyngitis Nausea, vomiting, diarrhea, GI upset

Tipranavir (Aptivus) (1,2)

Darunavir (Prezista) (1) Ritonavir (Norvir) (1,2)

600/100 RTV mg bid Used as a PK booster 100-200mg

300mg tabs 100mg caps; 80mg/mL

(1) Take with Food (2) Must be refrigerated ** All PIs except atazanavir can increase lipids and cause insulin resistance

Lipids, Insulin Resistance (Lypodystrophy)

Hypercolesterolemia
Usually hypertriglyceridemia, can have increased LDL and decreased HDL Treat with Fibric acid derivatives and certain HMGCoA reductase inhibitors

Insulin Resistance
Treat with diet/exercise, metformin, TZDs, insulin, sulfonylureas

Lipodystrophy Illustrations

Buffalo hump

Protease paunch Facial wasting

Dose adjustments to consider

Renally-eliminated NRTIs (except Abacavir) Adjust for CrCl <50 ml/min or dialysis Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Hepatic Metabolism NNRTIs PIs Adjust for certain inducers, substrates, or inhibitors of P450 system

Adjust for insufficiency Indinavir Fosamprenavir Atazanavir

Avoid Amprenavir oral soln Foasmprenavir (+/- ritonavir) Tipranavir

Reference: Drug product info and DHHS guidelines (see tables)

New ARV Targets Against HIV

Fusion Inhibitor
Fuzeon (Enfuvirtide, T-20)

Chemokine Receptor Antagonists

Marviroc (Selzentry) CCR5 or CXCR4 receptors on cell surface Virus will bind to one of the 2 receptors
Some patients virus will bind to either receptor

Marviroc blocks viral entry at CCR5 Dosed 300mg BID

150mg BID with P450 inhibitors 600mg BID with P450 inducers

Integrase Inhibitors
Raltegravir (Isentress) Dosed 400mg BID (1 tab BID) No induction or inhibition on CYP450 enzymes or Pgp Metabolized by UGT1A1 (glucuronidation)
Only affected by drugs that inhibit or induce UGTs (ie, rifampin)

Drug Interactions

Important Drug Interactions

Do NOT use Simvastatin, Lovastatin, Antiarrthymics, Midazolam, Triazolam, Ergot derivatives, Rifamin, St. Johns Wort, or Garlic with most PIs or DLV Do NOT combine Rifampin with PIs LPV/RTV may be dose increased and combined with Rifampin Conflicting data with EFV and NVP Use other P450 inducers with CAUTION when combining with PIs and NNRTIs Do NOT use Fluticasone or Alfuzosin with Ritonavir Caution with Azoles, Clarithromycin, Oral Contraceptives, Phenytoin, Carbamazepine, Phenobarbital, Methadone, PDE5 inhibitors, Atorvastatin, Beta blockers, when combined with PIs Avoid Herbal Products with Known or Suspected Interactions When combining Protease Inhibitors, Often Dose Adjustments are Necessary

How HIV weakens our defenses

The human immunodeficiency virus (HIV) weakens the body's immune defenses by destroying CD4 (T-cell) lymphocytes. These white blood cells normally help guard the body against attacks by bacteria, viruses and other germs. When HIV destroys CD4 cells, the body becomes vulnerable to many types of infections. These infections are called opportunistic because usually they only take opportunity to take hold in the body is when the immune defenses are weak

Opportunistic infection has developed. These types of infections include specific causes of pneumonia, diarrhea, eye infections and meningitis. Some of the causes of these opportunistic infections include Cryptococcus, reactivation of cytomegalovirus, reactivation of toxoplasma in the brain, wide-spread infection with Mycobacterium avium complex and Pneumocystis jiroveci (formerly called Pneumocystis carinii) in the lungs. Tuberculosis is one of the most common HIV/AIDS-related infection in the developing world.

ROLE OF THE PHARMACIST

The PHARMACIST is competent educationally and is involved in teaching and researching the mechanism of pathology of the disease, developing new drugs for its treatment including vaccines, promoting the awareness about the disease and how it can be prevented and control through the mean of retailing and distribution as medical representative and as a patient counselor

CONCLUSION
The number of people living with HIV and death caused by AIDS is still on increase globally Though the developments in recent years are revealing some hope and optimism, the ground realities are that there is no vaccine still available. The antiretroviral therapy which is available is not under the reach of the common man because the recommended regime and clinical testing procedure are elaborate, time consuming, costly and difficulty associated with anti retroviral therapy such as adherence, drug interaction, long term side effects and accessibility for indefinite period of time with the caution that not a single dose should be skipped during the period of therapy.

QUESTIONS
1. MATCHING TYPE 1.1 Saquinavir a. NRTI 1.2 Enfuvirtide b. NNRTI 1.3 Efavirenz c. PIs 1.4 Zidovudine d. Fusion Inhibitors 1.5 Marviroc e. Chemokine Receptor Antagonist 1.6 Raltegravir f. Integrase Inhibitor
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 2. TRUE OR FALSE Does all medications in the NRTI class carries a block box warning for LACTIC ACIDOSIS?

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 3. TRUE OF FALSE
When combining PIs with other classes or ARVs, dose adjustments are not necessary.

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 4-5 Two classes of ARVs wherein it inhibit reverse transcriptase enzyme

a. NRTI b. NNRTI c. PI d. Chemokine Receptor Antagonist e. Integrase Inhibitor

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 6. What country has the fastest growing population of HIV/AIDS victim? 7. Is HIV vaccine already available in the market? a. YES b. NO
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 8. Give one role of the Pharmacist in the current treatment of HIV/AIDS. 9. The most common HIV/AIDS related infection in the developing world a. pneumonia b. diarrhea c. tuberculosis d. meningitis
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 10. BONUS QUESTION

Can you get HIV/AIDS from kissing??? a. YES b. NO

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