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Session 6 BASIC HAART AND
DRUG INTERACTIONS
Mary Bishop RPH, AAHIVE
HIV/AIDS Clinical Pharmacist
UofL Healthcare Pharmacy
11/05/11
HIV life cycle
• http://www.youtube.com/watch?v=RO8MP3
wMvqg&feature=player_profilepage
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Goal of Therapy
• Maximally and durably suppress plasma HIV
viral load
• Reduce HIV-associated morbidity and prolong
survival
• Improve QOL
• Restore and preserve immune function
• Prevent HIV transmission
Starting Therapy
Recommendation
AIDS-Defining Illness
AI
CD4 < 350
AI
Pregnancy
HIV-Associated Nephropathy (HIVAN)
AI
AII
Hepatitis B Virus (HBV) co-infection
AIII
[when HBV treatment is indicated]
CD4 350-500
CD4 > 500
†
‡
Strength
A/BII†
B/CIII‡
Panel divided , 55% voted for strong recommendation (A) and 45% voted for moderate
recommendation (B) (A/B-II).
Panel divided, 50% favor starting antiretroviral therapy at this stage of HIV disease (B);
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50% view initiating therapy at this stage as optional (C) (B/C-III).
15 YEARS OF “HAART”
24 years since first drug
We now have :
7 Nucleoside/tide analogs
(4 combos)
5 Non-nucleoside analogs
(2 combos)
9 Protease Inhibitors
1 Fusion Inhibitor
1 CCR5 antagonist
1 Integrase Inhibitor
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What drug to use when?
• Guidelines
– http://AIDSinfo.nih.gov
– IAS-USA
– WHO
• Patient assessment and education
• Genotype
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Recommended HAART* in
Treatment Naïve Patients
*highly active ant-retroviral therapy
• 1 NNRTI + 2 NRTI’s
EFV + TDF + FTC (Atripla®)
• 1 PI (preferable PI/r) + 2NRTI’s
ATV/r + TVD
DRV/r + TVD
• 1 INSTI + 2 NRTI’s
RAL + TVD
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 37
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Panel also recommends that
medication selection…
• Individualized based on viral efficacy, toxicity, pill
burden, dosing frequency, drug-drug interaction
potential, resistance testing results, and co-morbid
conditions.
• Based on individual patient characteristics and
needs, in some instances, an alternative regimen
may actually be a preferred regimen for a patient.
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents Page 37
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NRTI Structures
Adenosine
Cytosine
Guanine
Thymine
Didanosine (ddI)
Zalcitabine (ddC)
Abacavir (ABV)
Zidovudine (ZDV)
Amdoxovir (DAPD)
Stavudine (d4T)
Lamivudine (3TC)
Tenofovir (TDF)
Emtricitabine (FTC)
Clin Ther 2000; 22: 685-708
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NRTI’s…
• Considered the backbone of HAART therapy
• All but Abacavir need dosing adjustments for
renal insufficiency
• All have black box warnings
• Short term side effects mostly GI related
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NRTI’s…
Zidovudine AZT (Retrovir®)
Didanosine ddI (Videx EC®)
Stavudine
d4T (Zerit®)
Lamivudine 3TC (Epivir®)
Emtricitabine FTC (Emtriva®)
Abacavir
ABC (Ziagen®)
Marrow suppression
Peripheral neuropathy
Peripheral neuropathy
Headache, Nausea
Headache, Nausea
Hypersensitivity
NRTI Combinations
•
•
•
•
Truvada (FTC/TNF) or TDV
Epzicom (ABC/3TC) or EPZ
Combivir (AZT/3TC) or CBV
Trizivir (ABC/3TC/AZT) or TZV
(No combination products should be used in renally impaired patients CrCl
<50ml/min)
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TDF (Tenofovir) Viread®
• Nucleotide Reverse Transcriptase
• 300mg Daily +/- food
• ADE
• Asthenia, HA, NVD, flatulence
• Renal insufficiency, Fanconi syndrome
• Osteomalacia, decrease in bone mineral density
• Activity against Hepatitis B
• Part of Truvada®, Atripla®, and Complera®
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FTC (Emtricitabine) Emtriva®
•
•
•
•
•
•
200mg daily +/- food
Dizziness, HA, Rash, insomnia
Hyper-pigmentation/skin discoloration
Also has activity against Hepatitis B
184V mutation
In Truvada®, Atripla®, and Complera®
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ABC (Abacavir) Ziagen®
• 300mg BID or 600mg Q Day +/- food
some cohort studies suggest increase risk of MI with recent or
current use of ABC but not substantiated with further studies
• HLA-B*5701
• Risk of “hypersensitivity reaction” combination of
symptoms
»
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»
Group
Group
Group
Group
Group
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Fever
Rash
GI symptoms
Malaise, fatigue
SOB, cough, or sore throat
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3TC (Lamivudine) Epivir®
•
•
•
•
•
150mg BID or 300mg daily +/- food
Minimal toxicity
Approved at 100mg to treat Hepatitis B
In Combivir®, Trizivir®, Epzicom®
184V mutation
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AZT (Zidovudine) Retrovir®
• Dosed 300mg BID +/- food
• Recommended in pregnancy (as Combivir®)
• ADE
– Bone marrow suppression, macrocytic anemia,
neutropenia
– GI intolerance, HA, insomnia, asthenia
– Nail pigmentation, palate discoloration
– Lactic acidosis and hepatic steatosis
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Zidovudine Pigmentation
Dark discoloration of the upper palate and nails
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NNRTI’s
• Class ADR’s
– Rash (Can treat through depending on severity)
– ^LFT’s, Hepatotoxicity
• Individual drugs
–
–
–
–
EFV (efavirenz) SUSTIVA®
NVP (nevirapine) VIRAMUNE®
ETV (etravirine) INTELENCE®
RPV (rilpivirine) EDURANT®
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EFV (Efavirenz) Sustiva®
• Dosed 600mg Q Day
• preferable bedtime
• Empty stomach to reduce side effects
• CNS side effects
• False + cannabinoid, benzodiazepine screening assay
• Pregnancy Category D
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NVP (Nevirapine) Viramune®
• 200mg daily x 14 day lead in period
then BID +/- food or
• Daily as XR formulation
• Rash  SJD
• Symptomatic hepatitis including
necrosis has been reported*
• Monitor LFT’s at 2,4,6 weeks then q 3
months
* ^risk in treatment naive women with CD4> 250mg/dl or treatment naïve men with CD4>400mg/dl
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Atripla®
Efavirenz 600mg+Emtricitibine 200mg+Tenofovir DF 300mg
• 1st time two companies
worked together
• 1 po Q HS on empty
stomach
• Not for patients with
CrCL<50ml/min
• Single co-pay?
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Second generation NNRTI’s
(effective in presence of K103N mutation)
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•
•
•
•
•
ETR (Etravirine)
INTELENCE®
200mg po BID
Rash, hepatotoxicity
Salvage therapy
CYP3A4 interactions
– TPV, FPV, ATV
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•
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•
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RPV (Rilpivirine)
EDURANT®
25mg daily w > 500kcal
Rash, depression
Don’t use if VL >100,000
D/I: PPI’s
Pregnancy Cat. B
Battle of monotherapy?
Atripla®
Empty stomach
Pregnancy Cat. D
Any viral load
CYP metabolism
CNS disengagement,
D/I with PI
DHHS stamp of approval
Complera®
With food
Pregnancy Cat B
VL <100,000
CYP metabolism
Depression
D/I with PPI
DHHS approval???
Protease Inhibitors
• Preferred in 2009
• Atazanavir (Reyataz®)
• Darunavir (Prezista®)
• Preferred in Pregnancy
• Lopinavir/r (Kaletra®)
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•
Alternates…
Saquinavir (Invirase®)
Ritonavir (Norvir®)
Indinavir (Crixivan®)
Nelfinavir (Viracept®)
Fosamprenavir (Lexiva®)
Tipranavir (Aptivus®)
Protease Inhibitors
• Changed HIV from fatal to chronic illness
• Class toxicities
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–
–
–
–
Short term- N/V/D
Long term- insulin resistance, lipodystrophy,
lipid abnormalities
LFT elevations
^risk of bleeding with hemophilia
• Most have drug interactions due to CYP metabolism
in the liver requiring dosage adjustments of PI’s or
other agent
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Elevated Lipids
(Cholesterol and Triglycerides)
• Occurs with EFV and PI’s
• May increase risk for coronary heart disease
• Treat through or stop medication
– “statins” (e.g. atorvastatin)
– Fibrate (e.g. fenofibrate or gemfibrozil)
• Prevention
– Stop Smoking
– Diet and exercise
– Fish Oil
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ATV (Atazanavir) Reyataz®
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•
•
•
Dose is 300mg/100mg ATV/r + food.
Lipid sparing if un-boosted
Do not use with PPI’s
Side effects (well tolerated)
• Indirect hyperbilirubinemia
• Nephrolithiasis
• PR prolongation
• Mutations at I50V, 84, and 88
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RTV (Ritonavir) Norvir®
• Potent CYP3A4 Inhibitor
• When used as lone PI, dose is 600mg BID (rare)
• Has 2 formulations
– Capsules require refrigeration +/- food
– Tablets must be taken with food, no refrigeration
• Side effects
– NVD
– Taste perversion
– Parasthesias-circumoral and extremities
• Mutations at 82 and 84
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DRV (Darunavir) Prezista®
• ARV Naïve dose
– 800mg/100mg po daily + food
• ARV experienced
– 600mg/100mg po BID + food
• Side effects
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–
–
–
Rash (sulfonamide moiety)
Diarrhea, Nausea
Headache
Fever
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MVC (Maraviroc) Selzentry®
• Only indicated for CCR5 tropic HIV-1 infection
• Dose is dependent on other drugs in the regimen
– 150mg BID +/- food
– 300mg BID +/- food
– 600mg BID +/- food
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MVC continued…
• Side effects
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–
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Abdominal pain
Fever
Dizziness
Musculoskeletal symptoms
Cough, URI
Orthostatic Hypotension
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Fusion Inhibitors
• Enfurvitide (Fuzeon ®)
T-20
• 90mg SQ q 12 h
• $$
• Injection site reactions
• Salvage therapy
• $$
Integrase Inhibitor
•
•
•
•
•
RAL (Raltegravir) Isentress®
400mg po BID +/- food
Approved as 1st line therapy
Metabolism is glucaronidation NOT CYP450
SE
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Nausea, Diarrhea
HA
Fever
CPK elevation
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Which Therapy is Best?
The regimen that the patient can take
every dose every day
At the same time.
The Realities of Adherence:
• Get it right the first time: Establish readiness before initiating ART
• Anticipate common causes of poor adherence not related to the
medication: Mental illness, drug use, homelessness, life instability,
poor clinic attendance
• Pill Fatigue: Even excellent adherence may wane over time;
consider pill burden and dosing frequency
• Tolerability: Side effects, drug interactions
• Wanted: Simple, tolerable, potent, effective, and forgiving ART
regimen
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CLINICAL SCENARIOS…
HIV Management
“Co-Medicators”
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Opportunistic infections
Malignancies
Drug dependence
Psychiatric disorders
Neurologic manifestations
Metabolic disorders
Opportunistic Infection
Prophylaxis and Treatment
• Pneumocystic jiroveci formerly
Pneumocystic carinii (PCP)
Prophylaxis (CD4+ cell count <200): Bactrim DS 1 PO QD
Treatment: Bactrim IV 15 mg/kg/d x 21 d
• Toxoplasmosis gondii
Prophylaxis (CD4+ cell count <100): Bactrim DS 1 PO QD
Treatment: Sulfadiazine and Pyrimethamine + folinic acid
Opportunistic Infection
Prophylaxis and Treatment
• Mycobacterium avium Complex
Prophylaxis (CD4+ cell count <50): Azithromycin 1200 mg PO Q week
Treatment: Clarithromycin and Ethambutol
• Candida albicans
Treatment: Fluconazole 100mg po x 7-14 days.
Maintenance: Optimum prevention is immune reconstitution, but oral
fluconazole is recommended for severe or frequent recurrence. Continuous
use is not associated with more resistance than episodic treatment. (ACTG
323)
Anxiolytics
• Avoid: triazolam and midazolam
• Consider: short-acting agents
-Lorazepam (Ativan®)
-Oxazepam (Serax®)
• Consider: Buspirone (Buspar®)
• Alprazolam (Xanax®) should be used cautiously
with ritonavir
Tuberculosis
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•
•
•
Rifampin (RIF) potent inducer of CYP
Avoid RIF and PIs
Rifabutin should be DOC
Adjust rifabutin dose with EFV, ATV, NFV, fPV,
IDV, RTV
Antidepressants
• Generally safe
• Some ARVs may potentiate TCAs, manifesting
in pronounced anticholinergic effects
• Desipramine (Norpramin®) should be avoided
• SSRIs most common agent of choice, safer in
overdose-start low and build as tolerated
Psychotropics
• Generally safe with few exceptions
• Area of drug development – best to consult
references with regards to new agents
• Concerns regarding metabolic disturbances
• Avoid pimozide (Orap®) with PIs
Anticonvulsants
• Phenobarbital: potent CYP inducer
• Phenytoin: highly protein bound (AVOID)
• CBZ: increased toxicity when combined with
PIs and/or CYP induction (AVOID)
• VPA: some studies have associated use with
increases in viral load?
• Consider: gabapentin, pregabalin, lamotrigine,
tiagabine, levotiracetam
Hypertension
• No significant interactions with typical antiHTN agents
• ACE-I, ARBs, diuretics, beta-blockers,
• calcium channel blockers with PIs-√,
• Avoid bepridil (Vascor®) with PI’s
Anti-arrhythmics
• Use very cautiously in combination with PI’s
• Amiodarone, encainide, flecainide,
propafenone, quinidine
Antihyperlipidemics
• Preferred agents for increased LDL:
Pravastatin (Pravacol®)
Atorvastatin (Lipitor®)
• Preferred agent for HyperTG:
Gemfibrozil (Lopid®)
Fenofibrate (Tricor®)
• Niacin appears safe – sustained release
product (Niaspan®) may be preferred agent
due to reduced incidence of hepatic
dysfunction, increased serum glucose
Erectile Dysfunction
• Sildenafil, vardenafil, tadalafil
• Cautions: reduced metabolism when
combined with PIs
• S: 25 mg q48h
• V: 2.5 mg q72h
• T: 10 mg q 72h
• Nitrates, nitrites, “Poppers”
Herbal Therapies
• St. John’s Wort
-IDV AUC <50%(CYP3A4 and pGP induction)
• Garlic
-Inhibition of CYP3A4; severe GI A/E with RTV
• Others: milk thistle, grapefruit juice, ginseng,
skullcap
Questions
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References
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www.CDC.gov/HIV
www.Medscape.com/hiv-aidshome
www.Hopkins-aids.edu
http:AIDSinfo.nih.gov
Netaccess/Micromedix
www.FAETC.org
www.lexi.com
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