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
3
4
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);
6
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
7
What drug to use when?
• Guidelines
– http://AIDSinfo.nih.gov
– IAS-USA
– WHO
• Patient assessment and education
• Genotype
8
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
9
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
10
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
11
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
12
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)
14
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®
15
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®
16
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
»
»
»
»
»
Group
Group
Group
Group
Group
1
2
3
4
5
Fever
Rash
GI symptoms
Malaise, fatigue
SOB, cough, or sore throat
17
3TC (Lamivudine) Epivir®
•
•
•
•
•
150mg BID or 300mg daily +/- food
Minimal toxicity
Approved at 100mg to treat Hepatitis B
In Combivir®, Trizivir®, Epzicom®
184V mutation
18
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
19
Zidovudine Pigmentation
Dark discoloration of the upper palate and nails
20
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®
21
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
22
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
23
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?
24
Second generation NNRTI’s
(effective in presence of K103N mutation)
•
•
•
•
•
•
ETR (Etravirine)
INTELENCE®
200mg po BID
Rash, hepatotoxicity
Salvage therapy
CYP3A4 interactions
– TPV, FPV, ATV
•
•
•
•
•
•
•
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®)
•
•
•
•
•
•
•
Alternates…
Saquinavir (Invirase®)
Ritonavir (Norvir®)
Indinavir (Crixivan®)
Nelfinavir (Viracept®)
Fosamprenavir (Lexiva®)
Tipranavir (Aptivus®)
Protease Inhibitors
• Changed HIV from fatal to chronic illness
• Class toxicities
–
–
–
–
–
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
28
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
29
ATV (Atazanavir) Reyataz®
•
•
•
•
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
30
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
31
DRV (Darunavir) Prezista®
• ARV Naïve dose
– 800mg/100mg po daily + food
• ARV experienced
– 600mg/100mg po BID + food
• Side effects
–
–
–
–
Rash (sulfonamide moiety)
Diarrhea, Nausea
Headache
Fever
32
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
33
MVC continued…
• Side effects
–
–
–
–
–
–
Abdominal pain
Fever
Dizziness
Musculoskeletal symptoms
Cough, URI
Orthostatic Hypotension
34
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
–
–
–
–
Nausea, Diarrhea
HA
Fever
CPK elevation
36
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
38
CLINICAL SCENARIOS…
HIV Management
“Co-Medicators”
•
•
•
•
•
•
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
•
•
•
•
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
54
References
•
•
•
•
•
•
•
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
55