HIV

1
HIV AIDS

• Brooke Y. Patterson, PharmD
• Clinical Asst. Professor of Pharmacy Practice
• UMKC School of Pharmacy
• February 6, 2005

2
Introduction

• In 2001, approximately 6000 young people were
  infected with HIV every day (5 persons every
  minute)
• Worldwide, more than 80 of HIV infections are
  acquired through heterosexual intercourse
• ¼ of Americans infected with HIV dont even know
  they have it
• Only 12 of the HIV patients worldwide who need
  treatment actually receive it

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4
HIV Testing

• Confidential and/or anonymous
• Conventional blood test
• ELISA-method
• Up to 2 weeks for results
• Conventional oral fluid test
• Same as blood test
• Rapid-testing
• Oral fluid
• Fingerstick
• Results available in 20 minutes
• A positive result MUST be confirmed by
  western-blot testing

5
Clinical Presentation

• Primary infection occurs within 2 weeks to 6
  months of acquiring HIV
• Fever
• Pharyngitis
• Lymphadenopathy
• Rash
• Myalgia/arthralgia
• Diarrhea
• Headache
• N/V
• Immunologic lag time for HIV test
• 3 months
• Clinical Latency asymptomatic 8-10 years
  (untreated)

6
Newly Diagnosed

• HIV test (confirm)
• Complete history, PE
• Opportunistic Infections
• Acute primary infection
• CD4 count
• NOT during primary infection
• HIV viral load
• CBC w/ differential
• BMP
• LFTs
• Lipid profile (including TGs)
• Hep B and Hep C testing
• HIV resistance testing (?)

7
Psychosocial Evaluation

• Substance abuse
• Psychiatric disorders
• Housing
• Support
• Work
• Ability to afford care, medications

8
Initiating Therapy
9
Indications for HAART
Department of Health Human Services. Panel of
Clinical Practices for Treatment of HIV
Infection. Guidelines for the use of
Antiretroviral Agents in HIV-Infected Adults
Adolescents. October 29, 2004.
10
Goals of Therapy

• Suppress HIV VL to lt50 copies/mL for as long as
  possible
• Improve quality of life
• Preserve future therapeutic options
• Restore immune function

11
Preferred Regimens

• Triple Therapy
• PI or NNRTI based
• Use of combination pills to decrease pill-burden

12
Comparison of Initial Therapies

• NNRTI-Based
• Less fat maldistribution and dyslipidemia than
  PIs
• Preserve PI class
• Low barrier to resistance/cross-resistance among
  NNRTIs
• Neuropsychiatric effects
• Pregnancy contraindication

• PI-based
• Preserve NNRTI class
• Survival data
• Metabolic complications
• CYP3A4 interactions

13
Highly Active Antiretroviral Therapy (HAART)
14
Timeline
1979
1983
1987
1991
1992
1995
2006
23 Medications 4 drug classes
The first cases of HIV/AIDS are identified.
AZT is the first antiretroviral approved by the
FDA
First clinical trial of multiple drug therapy
The virus is identified by the Institut Pasteur
(France)
10 million are infected by HIV worldwide
Saquinivir, the first PI is approved by the FDA
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1.
16
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
17
Efavirenz (Sustiva, EFV)

• 600mg PO QD with light snack (or empty stomach)
• Long half-life
• CNS-toxicity
• Hallucinations
• Disturbed dreams
• Disconnected feeling
• African-Americans vs. Whites
• Enzyme auto-induction
• Contraindicated with pregnancy
• Women of child-bearing age
• Barrier form of contraception
• False-positive UDS for marijuana
• TG abnormalities
• Rash

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Nevirapine (Viramune, NVP)

• 200mg QD X 1 week, then 200mg BID with or without
  food
• 400mg QD NOT FDA-approved
• Rash
• SJS (potentially fatal)
• Hepatotoxicity
• First 12-weeks of therapy
• Hepatitis C co-infection
• Women gt Men
• CD4 gt250 cells/µL
• Prevents mother?child transmission
• Resistance

19
Delaviridine (Rescriptor, DLV)

• No clinical utility

20
Nucleotide/Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
21
Class Adverse Effect(s)

• Pancreatitis
• Alcohol use
• Abdominal pain, diarrhea, nausea
• Lactic acidosis
• Acid-base disorder
• Women
• Obese
• Long-term exposure
• Nausea, mental status changes, sedation
• POTENTIALLY FATAL

22
Abacavir (Ziagen, ABC)

• 300mg BID or 600mg QD with or without food
• Hypersensitivity Reaction
• Fever
• N/V
• Malaise
• Myalgia/arthralgia
• Rash
• Respiratory difficulty
• First 2 months of therapy, gradual worsening of
  symptoms with each dose
• Do NOT rechallenge?next reaction could be FATAL
• Increased incidence in treatment-naive(?)
• High barrier to resistance
• Available in combination with lamivudine(Epzicom)
  and zidovudine lamivudine (Trizivir

23
Didanosine (Videx, ddI)

• Videx and Videx EC
• 400 mg QD on an empty stomach
• 30 minutes before or 2 hours after a meal
• Take with water only
• Reduce dose if lt60 kg or combined with tenofovir
• Peripheral Neuropathy
• 6 months to 1 year to resolve
• Diarrhea
• Improved with EC formulation
• Do NOT use with tenofovir or stavudine

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Emtricitabine (Emtriva, FTC)

• 200mg QD with or without food
• Nearly identical to lamivudine
• Activity against hepatitis B
• Skin discoloration
• African-americans
• Hyperpigmentation
• Palms of hands soles of feet
• Females gt males

25
Lamivudine (Epivir, 3TC)

• 300 mg QD with or without food
• Easily tolerated
• Activity against hepatitis B
• Resistance mutation M184
• Occurs rapidly if non-compliant
• Virus less fit to replicate

26
Stavudine (Zerit, d4t)

• 40mg BID with or without food
• Reduce dose if lt60 kg
• Peripheral neuropathy
• 6 months to 1 year to resolve
• Dyslipidemia
• Synergy with protease inhibitors
• Lipodystrophy
• Facial wasting buffalo humps
• Do NOT take with ddI

27
Tenofovir (Viread, TFV)

• 300mg QD with or without food
• Interactions with ddI, atazanavir
• Nucleotide reverse transcriptase inhibitor
• Fairly well-tolerated
• Activity against hepatitis B
• Do NOT give with ddI
• Virologic failure
• Nephrotoxicity
• Decline in CrCl gt50 in 17 cases (Patterson et
  al. 2005)
• Increased risk with IV drug users (Patterson et
  al. 2005)
• Hypophosphatemia
• Acute toxcity (Patterson et al. 2005)

28
Zidovudine (Retrovir, AZT)

• 300mg BID with or without food
• Bone marrow suppression
• Anemia
• Neutropenia
• May use Procrit
• Insomnia
• Dermatologic changes
• Dark skin may get darker, ashen
• Nail bed changes
• Lipodystrophy
• Prevents mother? child transmission
• Post-exposure prophylaxis

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Combination Products

• Truvada (emtricitabine/tenofovir)
• One tablet (200/300mg) PO QD
• Epzicom (abacavir/lamivudine)
• One tablet (600/300 mg) PO QD
• Combivir (zidovudine/lamivudine)
• One tablet (300/150 mg) PO BID
• Trizivir (zidovudine/lamivudine/abacavir)
• One tablet (300/150/300 mg) PO BID

30
Protease Inhibitors (PIs)
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Class Adverse Effect(s)

• Metabolic effects
• Hyperlipidemia
• Hypertriglyceridemia
• Lipodystrophy
• Facial wasting
• Peripheral fat wasting
• Accumulation of fat in belly, back
• Diabetes
• New onset
• Worsening

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Atazanavir (Reyataz, ATV)

• Dosing based on treatment experience
• Naïve 400mg PO QD with food
• Experienced 300mg PO QD plus ritonavir 100mg QD
  with food
• Drug interactions with antiretrovirals (reduce
  dose)
• Efavirenz
• Nevirapine
• Tenofovir
• Do NOT take with PPIs, histamine-receptor
  blockers, antacids
• Hyperbilirubinemia
• PR-interval elongation
• NO metabolic effects (unless boosted with
  ritonavir)

35
Fosamprenavir (Lexiva, FPV)

• Fosamprenavir? amprenavir (Agenerase)
• Dosing based on treatment experience
• Complicated dosing schemes
• Treatment-naïve
• Protease-naïve vs. protease-experienced
• Rash
• Sulfa-based
• Diarrhea
• Salvage-regimen

36
Indinivir (Crixivan, IDV)

• 800mg PO TID on an empty stomach or light
  (low-fat) snack OR 800mg PO BID with ritonavir
  100mg with food
• Kidney stones
• Increase water intake (48 oz/day)
• Crystallized indinivir
• Itchy and/or dry skin
• Ingrown toenails
• Hyperbilirubinemia

37
Lopinavir/Ritonavir (Kaletra, LPV/RTV)

• 3 capsules (133/33 mg) PO BID with food or 6
  capsules PO QD (treatment-naïve ONLY)
• Liver dysfunction
• Keep refrigerated until dispensed
• 2 months unrefrigerated

38
Nelfinavir (Viracept, NFV)

• 1250mg PO BID with a meal
• High-fat meal (20-50 calories)
• Abdominal pain
• Bloating
• Diarrhea
• Explosive, uncontrollable
• Calcium supplements
• Less with 625mg tablets than 250mg tablets
• Decreased efficacy of OCs
• Recommended for use in pregnancy

39
Ritonavir (Norvir, RTV)

• The Booster
• Boosting doses 100-400mg PO QD to BID with food
• MANY drug interactions
• Refrigerate until dispensed
• Bitter taste
• Chocolate
• Heptotoxicity
• Controversy Pricing

40
Saquinivir (Invirase, Fortovase, SQV)

• Fortovase soft-gel 1000mg PO BID with RTV
  100mg BID with food
• Invirase hard-gel 1600mg PO QD with RTV 100mg
  QD with food
• Diarrhea
• Fortovase gt Invirase (?)
• Recommended in pregnancy
• Refrigerate Fortovase NOT Invirase

41
Tipranavir (Aptivus, TPV)

• Newest PI
• Third generation non-peptidic protease
  inhibitors
• 500mg PO BID and RTV 200mg BID with food
• Refrigerate until dispensed
• 60-days at room temperature
• Hepatotoxicity
• Rash
• Oral contraceptives
• Sulfa allergy
• Salvage regimen

42
Fusion Inhibitors
43
Enfuvirtide (Fuzeon, T-20)

• 1 mL SQ BID
• Multi-step reconstitution process
• Injection-site reactions
• Itching
• Swelling
• Pain
• Nodules
• Salvage regimen
• Cost 2,152.21/ month

44
Dealing With Drug Side Effects
45
Fatigue

• Break-in period
• Physical vs. psychological
• Anemia
• Tips for patients
• Consistent sleep-wake schedule
• Exercise
• Eat healthy

46
Rash

• Nevirapine and nelfinavir
• Women gt Men
• Abacavir hypersensitivity
• Rash with other systemic symptoms
• Tips for patients
• Diphenhydramine for pruritis
• Unscented or oatmeal soap
• Avoid hot showers
• Protect from UV exposure

47
Peripheral Neuropathy

• Discontinue offending agent
• Pharmacologic treatments
• Amitriptyline (watch for drug interactions)
• Gabapentin
• L-acetyl carnitine (?)
• Tips for patients
• Loose-fitting shoes, socks
• Keep feet uncovered in bed
• Walking
• Massage feet

48
Diarrhea

• Break-in period
• Almost all medications
• Concern for dehydration, weight loss
• Calcium supplements
• Pharmacologic therapies
• Diphenoxylate/atropine (Lomotil)
• Loperamide (Immodium)
• Tips for patients
• Eat foods high in soluble fiber (oatmeal, bread)
• Avoid milk products
• Avoid greasy foods
• Plenty of fluids

49
Dry Mouth

• Effect sense of taste
• Increased risk of oral candidiasis (thrush)
• Tips for patients
• Avoid sugary foods, caffeinated beverages
• Suck on sugarless candy or chew sugarless gum
• Rinse mouth daily with salt water

50
Nausea Vomiting

• Break-in period
• Dehydration, weight loss
• Pharmacologic interventions
• Promethazine (Phenergan)
• 5HT3 antagonists
• Tips for patients
• BRAT diet
• Leave dry crackers by bed
• Chamomile tea, ginger ale, 7-up

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Medication Adherence
52
Medication Adherence

• Teamwork approach
• Readiness to start therapy
• EDUCATION on side effects
• Break-in period
• Simplifying regimens, use of combination pills
• Role of pharmacist

53
Monitoring Therapy
54
Visit Frequency

• Follow-up within 1-2 weeks from starting HAART
• ADRs
• Compliance
• Transmission prevention
• Follow-up every 3 months

55
Laboratory Monitoring

• Viral load
• 4 weeks after initiation of HAART
• 8-12 weeks thereafter
• Every 6-8 weeks until VL undetectable (lt50
  copies/mL)
• Every 3 months while stable
• Blips
• CD4
• 4 weeks after initiation
• Every 3 months while stable

56
Laboratory Monitoring

• CBC with differential
• BMS
• Anemia
• Electrolytes
• Renal function
• PO4
• Liver transaminases
• Medication-specific
• Urinalysis
• EKG

57
BREAK

• http//www.unfpa.org/aids_clock/main.htm

58
Resistance Testing
59
Genotypic Resistance Testing

• Mutations to genes that are target of
  antiretroviral drugs
• Mutational change? resistance
• Faster, cheaper
• Valid ONLY for meds being given at the time of
  test
• Resistant strains become minority species when
  drug pressure removed
• Best for patients NOT on PIs

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Example Genotypic Results

• NRTIs Resistance Mutation
• ZDV N
• ABC N
• ddI N
• 3TC Y M184I
• FTC Y M184I
• D4t N
• ddC Y M184I
• TFV N

61
Phenotypic Resistance Testing

• Measure ability of patients HIV to replicate in
  the presence of medication
• Compared to wild-type virus
• Amount of medication to inhibit virus compared to
  wild-type
• lt2-foldsusceptible
• More expensive, much longer to get results
• Does NOT take into account multiple medications

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Example Phenotypic Testing

• NRTIs Susceptibility Fold change
• ZDV 1.5
• ABC 20
• ddI 15
• 3TC 15
• FTC 20
• D4t 1.2
• ddC 20
• TFV 15

63
Virtual Phenotypic Test

• Hybrid of phenotypic and genotypic testing
• Determine how likely it is that each of your
  mutations will be resistant to HIV medications
• Updated computer database
• Refined improved

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Example Virtual Phenotypic Test

• NRTIs Fold change Cut-off Resistant
• ZDV 1.5 2.0 N
• ABC 20 10 Y
• ddI 15 18 N
• 3TC 15 18 N
• FTC 20 10 Y
• D4t 1.2 4.0 N
• ddC 20 10 Y
• TFV 15 8 Y

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Who Should Get Resistance Testing?

• Patients whose VL rises while on treatment
• Test while ON medication
• Patients who need to change meds due to side
  effects
• VL gt1000
• Pregnant women
• VL should be undectable throughout pregnancy

66
Therapeutic Drug Monitoring
67
Therapeutic Drug Monitoring

• Rationale
• Inter-patient variability
• Concentration lt-gt effect
• Utilization
• NNRTIs
• PIs
• Measure efficacy vs. toxicity
• Europe

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Scenarios For Use

• Drug-drug interactions
• Pathophysiologic abnormalities
• Pregnancy
• Treatment-experienced patients
• Lack of expected virologic response
• Clinical trials

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Limitations

• Impact on clinical outcome
• Lack of established therapeutic ranges
• Very expensive

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Therapeutic Drug Monitoring
Guidelines for the Use of Antiretroviral Agents
in the HIV-1 infected adults adolescents.
October 6, 2006.
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Drug Interactions
72
Overview

• Antiretrovirals, prescription, psychiatric, OTC,
  and herbal
• Protease Inhibitors and NNRTIs
• CYP 450
• 3A4
• Inhibitors and inducers
• 2D6
• P-glycoprotein
• Absolute contraindications vs. interactions
  requiring dosing adjustments

73
Antifungals

• Itraconazole (Sporanox), Ketoconazole
  (Nizoral), Voriconazole (Vfend)
• Avoid use with PIs
• Bi-directional inhibition
• Increased itraconazole and/or PI levels
• No voriconazole with efavirenz
• Fluconazole has fewer interactions and may be
  used with PIs, NNRTIs

74
Anti-Tuberculosis Medications

• Rifabutin (Mycobutin)
• Levels increased with PIs, must decrease
  rifabutin dose
• Level decreased with efavirenz, must increase
  rifabutin dose
• Rifampin (Rifadin
• Should NOT be co-administered with PIs
• Significantly reduces PI drug levels
• Efavirenz levels decreased 25 with use, must
  increase efavirenz dose

75
Antibiotics

• Clarithromycin (Biaxin)
• Drug levels increased with PI use. Adjust dose
  for renal function
• Drug levels decrease with efavirenz use. Do NOT
  use.

76
Oral Contraceptives

• Ethinyl estradiol
• Levels increased with PI and efavirenz use
  (except ritonavir), use lowest effective dose
• Fosamprenavirdo NOT use
• Levels significantly reduced with tipranavir,
  ritonavir usedo NOT use

77
Lipid-Lowering Agents

• Atorvastatin (Lipitor)
• Drug levels greatly increased with PI use. Use
  lowest effective dose and monitor closely
• Drug levels decreased with efavirenz
• Pravastatin (Pravachol), Rosuvastatin (Crestor)
• Preferred agent for use
• Simvastatin/Lovastatin (Zocor, Mevacor)
• Drug levels greatly increased with PI use. Do
  NOT use
• Drug levels decreased with efavirenz, adjust
  simvastatin dose appropriately

78
Anticonvulsants

• Carbamazepine (Tegretol), phenobarbital,
  phenytoin (Dilantin)
• PI drug levels decreased with use, cautious use
• Ritonavir increases carbamazepine levels, monitor
  closely
• Efavirenz doses greatly decreased, avoid use

79
Erectile Dysfunction Agents

• Sildenafil (Viagra), tadalafil (Cialis),
  vardenafil (Levitra)
• Drug levels largely increased with PI use, lowest
  effective dose and larger dosing interval should
  be used
• Recreational use among HIV () persons
• San Francisco
• RTV boosting
• Increased acquisition of STDs? (Curtis et. al.)

80
Psychotropic Medications

• Tricyclic antidepressants (amitriptyline,
  nortriptyline, etc.)
• Ritonavir greatly increases levels, use reduced
  dose
• Buproprion (Wellbutrin)
• Levels greatly increased with PIs and efavirenz
• Increased seizure risk
• Trazodone (Desyrel)
• Levels greatly increased with PIs leading to
  increased ADRs

81
Psychotropic Medications

• Triazolam (Halcion), midazolam (Versed)
• Levels greatly increased with PIs. Do NOT use
• Increased risk of respiratory depresssion,
  sedation, etc.
• Cautious use of alprazolam, lorazepam
• Fluoxetine
• May increase PI levels, consider use of other
  SSRIs

82
Antihypertensives

• Verapamil, diltiazem
• PI levels increase drug levels, cautious use
  (increased antihypertensive effect)

83
Herbal Supplements

• St. Johns Wort
• PIs and NNRTIs
• Decrease in blood levels of antiretroviral
  medications
• Treatment failure

• Additional herbs with demonstrated interactions
• Betel Nut
• Chili Pepper
• Devils Claw
• Dong quai
• Garlic
• Ginkgo
• Ginseng
• Guar gum
• Kava
• Papaya
• Valerian
• Yohimbe

84
BREAK

• http//www.unfpa.org/aids_clock/main.htm

85
Cases
86
WF is a 23 yo AAM who was referred to clinic
after testing positive for HIV at a rapid-testing
center
Current Meds None Allergies PCN (hives)
Vitals BP 120/72 mmHg Pulse 88 Temp 99
F Weight 180 lb. Height 55 Sexual History
MSM, unprotected sex, same 2 partners in last 6
months. Anal-receptive intercourse.
Oral-receptive intercourse. No history of STDs
in past. SH EtOH (), Marijuana (-), Crystal
Meth (-), Cocaine (-), Other illicit drugs
(-) PMH Not significant
87

• Laboratory Data (drawn 2/1/06)
• Sodium 138 (135-145) HIV () (ELISA method)
• Potassium 4.2 (3.5-5.0) HIV () (Western blot)
• Chloride 96 (95-110) CD4 190 cells/mL
• CO2 22 (20-29) VL 180,000 copies/mL
• SrCr 0.9 (0.8-1.4)
• BUN 12 (7-20)
• Glucose (fasting) 95 Gonorrhea (penile) -
• AST 52 (8-40) Chlamydia (penile) -
• ALT 88 (12-65)
• PE
• Chest Normal S1, S2. Breath sounds normal
  bilaterally. No ronchi, rales, wheezing
• HEENT Normal conjunctiva. Normal fundoscopic
  exam.
• Derm WNL
• Abdominal Normal bowel sounds
• Genital WNL
• Anus Mild erythema

88
JJ is a 32 yo WM who returns to clinic for
3-month follow-up. He has recently started
working-out more and has started a couple of
supplements

• Current Meds Allergies Sulfa (rash)
• Efavirenz 600mg QD
• Tenofovir/emtricitabine 300/200mg QD
• Lisinopril 10mg QD
• Atenolol 25mg QD
• ProteinMAX 1 tbsp QID with food
• Energy Pro 1 tablet daily
• Vitals
• BP 148/98 mmHg
• Pulse 70
• Temp 99 F
• Weight 210 lb.
• Height 57
• Sexual History MSW, married (wife is HIV(-)),
  protected sex. Would like to conceive a child.
• SH EtOH (-), Marijuana (-), Crystal Meth (-),
  Cocaine (-), Other illicit drugs (-)

89

• PMH
• Diagnosed with HIV 2002, initial CD4 300, lowest
  150
• HTN diagnosed 2004
• Hyperlipidemia (untreated)
• Laboratory Data (drawn 2/2/06)
• Sodium 135 (135-145)
• Potassium 4.8 (3.5-5.0)
• Chloride 96 (95-110) CD4 300 cells/mL
• CO2 22 (20-29) VL 80,000 copies/mL
• SrCr 1.8 (0.8-1.4)
• BUN 20 (7-20) FLP
• Glucose (fasting) 110 Total cholesterol 220
• AST 32 (8-40) HDL 50
• ALT 16 (12-65) LDL 150
• TGs 200
• PE WNL