ARVs: What We Have and What is Coming

1
ARVs What We Have and What is Coming

• Michael Thompson PharmD, BCNSP
• Professor of Pharmacy Practice
• Florida AM University
• Tallahassee, Florida

2
Disclosure of Financial Relationships

• This speaker has no significant financial
  relationships with commercial entities to
  disclose.

This slide set has been peer-reviewed to ensure
that there are no conflicts of interest
represented in the presentation.
3
Lecture Objectives

• Upon completion of this lecture the participant
  should be able to
• Identify currently available antiretroviral
  agents and discuss
• Mechanisms of action
• Common Adverse Effects
• Drug Interactions
• New Drugs and Potential Effects on Current
  Management

4
HIV Life Cycle
Fusion Inhibitors
Protease inhibitors (PIs)
NRTIs and NNRTI

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

5
ART Options

• NRTIs (Nucleoside OR Nucleotide Reverse
  Transcriptase Inhibitors, aka Nukes)
• NNRTIs (Non-Nucleoside Reverse Transcriptase
  Inhibitors, aka Non-Nukes)
• PIs (Protease Inhibitors)
• Fusion (or Entry Inhibitors)
• ART agents in additional classes
• currently in development
• Vaccines against HIV in the distant
• future?

6
Goal of Antiretroviral Therapy

• To achieve maximum and durable suppression of HIV
  replication
• Interpreted to mean an HIV RNA level in plasma
  that is less than the lower limit of quantization
  (i.e. undetectable)
• Increase in CD4 lymphocytes
• Improved quality of life
• Decreased morbidity and mortality

7
Goal of Therapy continued

• Decreasing viral load below level of sensitivity
  depends upon assay procedure
• RTPCR (Amplicor)---
• Versant----
• Nuclisens---
• Should be achieved within 16-24 weeks Should see
  a 1log10 reduction within 8 weeks
• Increase in CD4
• Adequate suppression is an increase by 100-150
  cells/mm3 per year

8
Tools to Achieve Goals

• Maximal adherence to prescribed regimens
• Rational sequencing of drugs
• Resistance Testing

9
DHHS HIV Treatment Guidelines
Hit Hard, Hit Early CD4 20,000
Hit Hard, Hit Later CD4 55,000
Hit Hard, Hit Even Later CD4
100,000
10
Timeline of ARV Approvals
1987 Zidovudine
1987 1st NRTI Approved
1991 Didanosine 1992 Zalcitabine 1994
Stavudine
1995 1st PI
1995 Lamivudine, Invirase
1996 1st NNRTI
1996 Nevirapine, Ritonavir, Indinavir
1997 Delavirdine, Nelfinavir, Fortovase 1998
Abacavir, Efavirenz 1999 Amprenavir 2000
Lopinavir/ritonavir 2001 Tenofovir
2003 1st Fusion Inhibitor
2003 T-20, Atazanavir, Emtricitabine,
Fosamprenavir 2005 Tipranavir 2006 Darunavir
The Future Entry inhibitors, Integrase
inhibitors,chemokine receptor inhibitors, others
11
Nucleoside/Nucleotide Reverse Transcriptase
Inhibitors (NRTIs)
Agent
Approved

• Zidovudine (AZT, ZDV, Retrovir?)
  3/87
• Didanosine (ddI, Videx?, Videx EC?) 10/91
• Zalcitabine (ddC, Hivid?) 6/92
• 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

A nucleotide reverse transcriptase inhibitor
12
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

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

13
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

14
Fusion Inhibitor

• Agent Approved
• Enfuvirtide (T-20, Fuzeon?) 3/03

15
Multi-class Product

• Atripla (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!

16
Choice of ARVs for Treatment of the ARV-Naïve
Patient1

• Guidelines provided preferred and alternative PI
  or NNRTI-based regimens for treatment-naïve
  patients
• Once patients have been a regimen, new regimens
  are constructed with the use of resistance
  testing, history of ARV use and tolerability
• Refer to the AETC reference card for a list of
  preferred and alternative regimens

1. October 10th, 2006 Department of Health and
Human Services Guidelines for the Use of
Antiretroviral Agents in HIV-infected Adult and
Adolescents Available at www.aidsinfo.nih.gov
17
Initial Treatment Preferred ComponentsDHHS
Guidelines October 11, 2006
NNRTI Option
NRTI Options
OR

• Tenofovir emtricitabine
• Zidovudine lamivudine

PI Options

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

Department of Health and Human Services
Guidelines for the Use of Antiretroviral Agents
in HIV-infected Adult and Adolescents. Otoberr
10, 2006. Available at www.aidsinfonih.gov.
Accessed October 12, 2006.
18
Regimens NOT Recommended
19
Regimens NOT Recommended
20
Regimens NOT Recommended
21
Choice of ARVs for Treatment of the ARV-Naïve
Patient

• ACTG 5095
• Higher failure rates with Trizivir (21)
  compared to Trizivir /efavirenz or
  Combivir/efavirenz arms (11)

1. Gulick et al. 2nd IAS Conference. Paris,
France. July 13-16, 2003.
22
Problems Associated with Antiretrovirals

• Adverse Effects
• Drug Interactions
• Resistance
• Genotyping
• Phenotyping

23
ARV Adverse Effects
24
NRTI Mitochondrial Toxicity

• MOA Inhibition of mitochondial DNA polymerase-?,
  ? oxidative metabolism, ? ATP generation
• Implicated in lactic acidosis with hepatic
  steatosis
• Other possible manifestations
• Myopathy (AZT)
• Neuropathy (d4T, ddI, ddC)
• Lipoatrophy (d4T)
• Pancreatitis (ddI)

25
HIV/HAART Toxicities Lactic Acidosis

• Rare but potentially fatal syndrome linked to
  prolonged use of NRTIs
• Symptoms include lethargy, fatigue, abdominal
  pain, respiratory distress
• Etiology mitochondrial dysfunction, possibly due
  to inhibition of key mitochondrial replication
  enzyme by antiretroviral agents
• Risk Factors
• Stavudine and didanosine use, pregnancy, female
  gender, obesity

26
Mechanism of Development of Lactic Acidosis in
HAART
27
Mechanism of NRTI Associated Lactic Acidosis
Specifics

• During normal glycolysis, glucose is converted to
  pyruvate in the cytosol and is transferred into
  the mitochondria
• Once the pyruvate is in the mitochondria, most of
  it is converted into acetylcoenzyme A, which in
  turn enters the tricarboxylic acid cycle to form
  NADH (nicotinamide adenine dinucleotide)
• NADH is used by the mitochondria to produce ATP
  through oxidative phosphorylation Dna polymerase
  is inhibited in the presence of NRTIs which
  diminishes mitochondrial function (especially
  oxidatiave phosphorylation)

28
continued

• Pyruvate and NADH accumulate and the conversion
  of pyruvate to lactate is enhanced
• Impaired oxidation leads to decreased fatty acid
  oxidation resulting in accumulation of free fatty
  acids
• Free fatty acids are converted to triglycerides
  and accumulate in liver causing hepatic steatosis

29
Adverse Effects Hepatotoxicity

• Hepatotoxicity
• Defined as 3 to 5 times increase in serum
  transaminases with or without clinical hepatitis
• All marketed NNRTIs and Protease Inhibitors have
  been associated with elevations in transaminases
• Of the NNRTIs, nevirapine has highest incidence
  of hepatoxicity and patients should be monitored
  especially throughout the first 18 weeks
  Patients with hepatitis B and C may be at
  increased risk.
• The two week lead in with nevirapine may reduce
  incidence of hepatotoxicity. Patients should be
  monitored every 2 weeks for the first month then
  monthly for the first 18 weeks. If rash occurs,
  patients should be monitored for hepatotoxicity
  as well.

30
Adverse Effects Hepatotoxicity

• Protease Inhibitors can cause hepatoxicity at ANY
  time during therapy
• Co infection with Hepatitis C or B, alcohol and
  stavudine use can increase potential for toxicity

31
Hepatotoxicity

• RTV use linked to increased risk of severe
  hepatotoxicity
• Increased LFTs observed with all PIs
• More common in pts with chronic viral hepatitis
  (HBV, HCV)
• Data do not support withholding PIs from
  co-infected patients with HBV or HCV

Sulkowski, JAMA 2000 28374
32
Adverse Effects NRTIs

• Abacavir - hypersensitivity reaction
• Didanosine - GI intolerance, pancreatitis,
  peripheral neuropathy (PN)
• Emtricitabine hyperpigmentation, skin
  discoloration
• Stavudine - PN, pancreatitis, lipodystrophy,
  dyslipidemia
• Tenofovir - headache, GI intolerance, renal
  impairment
• Zidovudine - headache, GI intolerance, bone
  marrow suppression

Black Box Warning- Lactic acidosis and hepatic
steatosis. Pregnant women may be at increased
risk for lactic acidosis and liver damage when
treated with stavudine didanosine. This
combination should be avoided in pregnant women,
if possible.
33
Abacavir hypersensitivity

• Black Box Warning
• Occurs in 5-8 of people taking abacavir
• Most common symptoms
• Fever, rash, nausea, fatigue, GI and URI symptoms
• Onset usually first two weeks of therapy
• Can be fatal if continued or restarted and should
  NEVER re-challenged
• Patient counseling and follow-up mandatory

34
Adverse Effects NNRTIs

• All NNRTIs
• Rash
• Increased liver function tests
• Nevirapine
• Hepatotoxicity (CD4 250? and 400 ?)
• Rash including Stevens-Johnson syndrome
• Use caution in discontinuing in patients on
  tenofovir, lamivudine, or emtricitabine, in HBV
  co-infected patients
• Efavirenz
• Neuropsychiatric effects (vivid dreams,
  nightmares, hallucinations, dizziness)
• Teratogenic in non-human primates (Pregnancy
  Category D)

35
Steven Johnson Syndrome or Toxic Epidermal
Necrolysis
http//www.fromthewilderness.com/images/stevenJohn
sonSyndrome2.jpg
36
Adverse Effects PIs

• All PIs
• GI intolerance
• Dyslipidemia
• Insulin resistance and diabetes
• Lipodystrophy
• Elevated liver function tests
• Possible increased bleeding risk in hemophiliacs
• Drug-drug interactions

37
Adverse Effects PIs

• Amprenavir, fosamprenavir, darunavir
  sulfonamide derivative potential for cross
  hypersensitivity with other sulfa drugs
• Amprenavir oral solution CI, in pregnancy,
  children
  renal failure, patients treated with disulfiram
  or metronidazole
• Atazanavir - hyperbilirubinemia, PR interval
  prolongation
• Indinavir nephrolithiasis, alopecia,
  paronychia, cheilitis, dermatitis,
  hyperbilirubinemia, HA, asthenia, blurred vision
• Lopinavir/ritonavir ??? diarrhea

38
Adverse Effects PIs

• Nelfinavir - ??? diarrhea
• Saquinavir- GI intolerance
• Tipranavir rash (contains sulfonamide
  derivative), hepatotoxicity, ??? lipids,
  associated with reports of fatal and non-fatal
  intracranial hemorrhage

39
Lipodystrophy
40
HAART Toxicities Lipodystrophy

• Body habitus changes
• Central fat accumulation
• Peripheral fat wasting
• Risk factors
• Female gender
• Older age
• HAART
• Protease Inhibitor use

41
Lipodystrophy
http//www.thebody.com/pinf/wise_words/mar05/lipod
ystrophy.html?m89o
42
Proposed Case Definition of Lipodystrophy

• Primary Characteristics
• Age 40 years
• HIV infection 4 years
• AIDS (Class C)
• Increased waist hip ratio
• Decreased HDL
• Change in anion gap

• Secondary Characteristics
• Increased total cholesterol
• Increased triglycerides
• Decreased lactate

http//www.hivforum.org/publications/Lipodystro
phy.pdf
http//www.med.unsw.edu.au/nchecr
43
Lipodystrophy Unclear Etiology

• Mitochondrial toxicity?
• Interference w/ adipocyte differentiation?
• Pro-inflammatory activation of the immune system
  during reconstitution?

44
Lipodystrophy Syndrome NRTIs versus PIs
PIs
NRTIs d4TZDV
Intra-abdominal fat Cholesterol
TG Insulin resistance
Lactic acid
SC fat wasting TG Buffalo hump
John M, et al. Antiviral Ther. 200169-20.
45
Lipodystrophy Treatment Options

• Switch PI to NNRTI or to all NRTI regimen
• Anti-hyperglycemic agents
• Metformin and Thiazolidindiones
• Growth hormone

46
Lipodystrophy Illustrations
Buffalo hump
Facial wasting
Crix belly
http//www.hivandhepatitis.com/recent/lipo/fataccu
mulation/1.htmlbuf
47
Severe Wasting
http//bayloraids.org/atlas/images/14.jpg
48
Facial Wasting
http//www.emedicine.com/derm/topic877.htmsection
pictures
49
Treatment of Facial WastingSculptra
http//www1.sculptra.com/US/hcp/Works.jsp
50
Bone Disorders in HIV Disease

• Osteonecrosis
• Death of bone tissue as resulting from
  circulatory insufficiency
• Usually involves femoral heads
• Increased frequency with introduction of HAART
• Diagnosis imagining
• Treatment surgical joint replacement
• Osteoporosis
• Bone demineralization
• Small reports of osteopenia and osteoporosis seen
  mainly with PI regimens
• Diagnosis X-ray or DEXA
• Treatment consider bisphosphonate drug with
  frank osteoporosis

51
HIV/HAART Toxicities Lipid Abnormalities

• Low HDL, high LDL and TGs
• Hypertriglyceridemia risk of pancreatitis
• Generally treated w/ fibrates and/or statins
• Inconsistent results from switch studies
• Beware of drug interactions, risk of myositis
• Avoid lovastatin or simvastatin

Guidelines for the Evaluation and Management of
Dyslipidemia in Human Immunodeficiency Virus
(HIV) Infected Adults Receiving Antiretroviral
Therapy Recommendations of the HIV Medicine
Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group.
Clin Infect Dis. 200337613-627 (Available
online at http//www.idsociety.org/Content/Navigat
ionMenu/Resources/HIVMA/Practice_Guidelines2/Pract
ice_Guidelines.htm)
52
HIV/HAART Toxicities Insulin Resistance

• Progression to frank diabetes mellitus possible
• Monitor with fasting glucose values
• Improvement often seen with switching out of
  PI-based regimens
• Some success w/ metformin (Glucophage)

53
Mechanisms of Drug Interactions
54
Why are HIV/AIDS Patients at Risk?

• Use of 3 and 4 drug antiretroviral regimens
• Multiple agents for treatment/prevention of
  various opportunistic infections
• Patient living longer and being treated for other
  chronic diseases (e.g. diabetes, CAD)
• Many antiretroviral agents have a profound effect
  on the cytochrome P450 enzyme system

55
Factors Affecting Concentration of Antiviral
Drug at its Site of Action
Absorption
Metabolism
CYPs P-gp
Oral AdministrationDrug (tablet/capsule)
Dissolution
GI MUCOSA
CYP3A4/5 CYP2B6 CYP2C19 P-gp
SYSTEMIC CIRCULATION
PIs NNRTIs
ProteinBoundDrug
FreeDrug
Distribution
TISSUES Bound Drug Free Drug

• TARGET CELL
• NRTIs (Intracellular Phosphorylation)
• Protease Inhibitors
• NNRTIs

Excretion
URINE BILE
http//www.clinicaloptions.com/
56
Effect of ARVs on Drug Metabolism
3A4
2C19
2D6
2C9
1A2
2E1
2A6
2B6
2C8
Inhibited by ATV
Fichtenbaum CJ. Clin Pharmacokinet.
2002411195-1211 Product labels.
57
Other Inhibitors and Inducers of Drug Metabolism

• Rifampin
• Rifabutin
• Phenobarbital
• Carbamazepine
• Phenytoin
• Cimetidine
• Omeprazole
• Fluoxetine

• Clarithromycin
• Erythromycin
• Non-DHP CCBs
• Azole Antifungals
• Isoniazid
• Ciprofloxacin
• Grapefruit juice
• Amiodarone

58
Drug Interactions HAART

• Nucleoside and Nucleotide drugs not eliminated
  via cytP450 therefore these interactions are
  minimal
• Drug interactions here may occur via other
  mechanisms (e.g GI absorption, renal elimination)

59
Effects of Food on Absorption of Antiretrovirals

• Didanosine
• Levels decrease by 55
• Take ½ hour before or 2 hours after meals
• Efavirenz
• Empty stomach, food increases levels as high as
  39-79
• Amprenavir
• High fat meal decreases blood levels
• Can take with food but avoid high fat
• f-Amp not affected as much

60
Food Effects continued..

• Ritonavir
• Take with food increases bioavailability
• Indinavir
• Food decreases levels by 77 (unless boosted)
• Take 1 hr before or 2 hr after or may take with
  skim milk or low fat meal
• Nelfinavir
• Levels increase 2-3 fold with food Take with food

61
Food Effects continued..

• Saquinavir (eg Fortovase, Invirase)
• Levels increase 6-fold if taken with food
• Take with or up to 2 hours after a meal as sole
  PI or with RTV
• Lopinavir/Ritonavir (Kaletra)
• Take with food
• AUC increased when taken with food

62
Examples of Noted Interactions Between
Antiretrovirals

• Efavirenz and Nevirapine
• Decrease atazanavir levels
• Tenofovir and ddI
• ddI levels are elevated (exact mechanism not
  known fully)
• Recommend 250mg ddI-EC (60 kg)
• Some reports to suggest decreased virologic
  control when this combination used as NRTI
  backbone with EFV or NVP

63
Antiretroviral Interactions continued

• Tenofovir and atazanavir
• Atazanavir levels are decreased
• Tenofovir concentrations increase
• Atazanavir should be boosted with RTV when
  combined
• Does not seem to be clinically significant with
  PIs such as lopinavir/ritonavir (Kaletra)
• Tenofovir may compete for tubular secretion for
  wide variety of drugs as well

64
Nonnucleoside Interactions

• Drugs involved
• Efavirenz can induce or inhibit CYP3A4 (most
  often acts as an inducer and can also induce
  others)
• Nevirapine acts as an inducer to CYP3A4
• Delavirdine acts as an inhibitor of CYP3A4

65
NRTI Drug Interactions

• Zidovudine
• Agents that cause additive bone marrow
  suppression (i.e. ganciclovir, flucytosine,
  pentamidine)
• Antagonism with stavudine (competition for
  intracellular activation)
• Didanosine (ddI)
• Inhibition of absorption of other agents due to
  ddI buffer in Videx (FQs, tetracyclines,
  dapsone, ketoconazole, indinavir, delavirdine)
• Ribavirin significantly ? ddI levels-do not use
  together

66
NNRTI Drug Interactions

• All NNRTIs are metabolized by the CYP3A4 enzyme
• Delavirdine can inhibit CYP3A4 enzyme
• Nevirapine can induce CYP3A4
• Efavirenz can inhibit or induce CYP3A4 enzyme

67
NRTI Drug Interactions

• Zidovudine
• Agents that cause additive bone marrow
  suppression (i.e. ganciclovir, flucytosine,
  pentamidine)
• Antagonism with stavudine (competition for
  intracellular activation)
• Didanosine (ddI)
• Inhibition of absorption of other agents due to
  ddI buffer in Videx (FQs, tetracyclines,
  dapsone, ketoconazole, indinavir, delavirdine)
• Ribavirin significantly ? ddI levels-do not use
  together

68
NRTI Drug Interactions

• Didanosine, Stavudine, Zalcitabine
• Agents causing additive neurotoxicity
  (vincristine, cisplatin, isoniazid)
• Agents causing additive pancreatoxicity (alcohol,
  pentamidine, valproic acid)
• Abacavir
• Metabolized by alcohol dehydrogenase (alcohol can
  increase abacavir levels and toxicity)

69
Protease Inhibitor Interactions

• All PIs inhibit CYP3A4
• Ritonavir is the most potent inhibitor while
  Saquinavir is the least potent
• Ritonavir can inhibit other cytochrome P450
  inhibitors and can induce CYP1A2
• Note Fusion inhibitors not metabolized by these
  systems

70
Drugs That Should Not Be Given With PIs

• Simvastatin
• Lovastatin
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Bepridil

• St. Johns Wort
• Rifampin (except ritonavir)
• Rifapentine
• Midazolam
• Triazolam
• Ergot alkaloids

• Additionally the following should not be given
  with ritonavir amiodarone, flecainide,
  propafenone, quinidine
• Proton pump inhibitors and Irinotecan should not
  be used with atazanavir

71
Medications Contraindicated with Protease
Inhibitors
72
Rifabutin Use with PIs
73
Interaction Between Atazanavir Omeprazole

• N 48 HIV(-) subjects
• ATV exposures substantially reduced by
  coadministration with OMP 40 mg
• Not corrected by increased ATV dose or 8 oz cola
• OMP exposures not significantly altered
• Effect of OMP 20 mg (OTC dose) not known
• Do not coadminister

Agarwala S, et al. CROI 2005. Abstract 658.
74
Fluticasone and Ritonavir (Flovent and Flonase)

• Fluticasone induced Cushings Syndrome
• Fluticasone is a 3A4 substrate and RTV a 3A4
  inhibitor

Gupta SK. CID 200235e69-e71
75
Drug Interactions with Drugs Used in Treating
Addiction

• Methadone
• Efavirenz and nevirapine decreases methadone
  levels Delavirdine effects unknown
• Abacavir decreases methadone clearance
• Methadone decreases stavudine levels but
  increases zidovudine
• PIs decrease levels and patients can have
  symptoms of withdrawal

76
ARV Interactions with Recreational Drugs
77
ARV Interactions with Recreational Drugs
78
Herbal and Nutraceutical Interactions with CYP450
3A4 Isoenzyme

• Echinacea
• Garlic pills
• Grapefruit juice
• Seville orange juice
• Milk thistle
• St. Johns wort

Will alter the metabolism of substrates of 3A4
system. Interactions have clinical significance
http//www.prn.org/prn_nb_cntnt/vol7/num1/pau_sum.
htm
79
Drug Interaction Resources

• www.hiv-druginteractions.org
• www.hivinsite.ucsf.edu
• www.medscape.com/px/hivscheduler
• www.aidsinfo.nih.gov
• (DHHS HIV Treatment Guidelines, TB Guidelines)

80
Summary