session 6 basic haart and drug interactions mary bishop rph, aahive hiv/aids clinical pharmacist...
TRANSCRIPT
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Session 6 BASIC HAART AND DRUG INTERACTIONS
Mary Bishop RPH, AAHIVEHIV/AIDS Clinical PharmacistUofL Healthcare Pharmacy
11/05/11
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HIV life cycle
• http://www.youtube.com/watch?v=RO8MP3wMvqg&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
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Starting Therapy
Recommendation StrengthAIDS-Defining Illness AI
CD4 < 350 AI
Pregnancy AI
HIV-Associated Nephropathy (HIVAN)
AII
Hepatitis B Virus (HBV) co-infection [when HBV treatment is indicated]
AIII
CD4 350-500 A/BII†
CD4 > 500 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); 50% view initiating therapy at this stage as optional (C) (B/C-III). 6
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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 Inhibitors1 Fusion Inhibitor1 CCR5 antagonist1 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’sEFV + TDF + FTC (Atripla®)
• 1 PI (preferable PI/r) + 2NRTI’sATV/r + TVDDRV/r + TVD
• 1 INSTI + 2 NRTI’sRAL + 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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Adenosine
Didanosine (ddI)
Tenofovir (TDF)
Cytosine
Zalcitabine (ddC)
Lamivudine (3TC)
Emtricitabine (FTC)
Guanine
Abacavir (ABV)
Amdoxovir (DAPD)
Thymine
Zidovudine (ZDV)
Stavudine (d4T)
Clin Ther 2000; 22: 685-708
NRTI Structures
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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®) Marrow suppressionDidanosine ddI (Videx EC®) Peripheral neuropathy Stavudine d4T (Zerit®) Peripheral neuropathyLamivudine 3TC (Epivir®) Headache, NauseaEmtricitabine FTC (Emtriva®) Headache, NauseaAbacavir ABC (Ziagen®) Hypersensitivity
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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 +/- foodsome 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 1 Fever» Group 2 Rash» Group 3 GI symptoms» Group 4 Malaise, fatigue» Group 5 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)
• 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
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Battle of monotherapy?
Atripla®Empty stomachPregnancy Cat. DAny viral loadCYP metabolismCNS disengagement, D/I with PIDHHS stamp of approval
Complera®With foodPregnancy Cat BVL <100,000CYP metabolismDepressionD/I with PPIDHHS approval???
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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®)
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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
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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®
• 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– 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– 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• $$• Injection site reactions• Salvage therapy• $$
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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
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Which Therapy is Best?
The regimen that the patient can take every dose every day
At the same time.
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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…
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HIV Management“Co-Medicators”
• Opportunistic infections• Malignancies• Drug dependence• Psychiatric disorders• Neurologic manifestations• Metabolic disorders
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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 gondiiProphylaxis (CD4+ cell count <100): Bactrim DS 1 PO QD
Treatment: Sulfadiazine and Pyrimethamine + folinic acid
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Opportunistic Infection Prophylaxis and Treatment
• Mycobacterium avium ComplexProphylaxis (CD4+ cell count <50): Azithromycin 1200 mg PO Q weekTreatment: Clarithromycin and Ethambutol
• Candida albicansTreatment: 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)
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Anxiolytics
• Avoid: triazolam and midazolam • Consider: short-acting agents
-Lorazepam (Ativan®) -Oxazepam (Serax®)
• Consider: Buspirone (Buspar®)• Alprazolam (Xanax®) should be used cautiously
with ritonavir
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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
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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
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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
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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
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Hypertension
• No significant interactions with typical anti-HTN agents
• ACE-I, ARBs, diuretics, beta-blockers, • calcium channel blockers with PIs-√, • Avoid bepridil (Vascor®) with PI’s
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Anti-arrhythmics
• Use very cautiously in combination with PI’s • Amiodarone, encainide, flecainide,
propafenone, quinidine
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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
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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”
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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
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Questions
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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