Session 6 BASIC HAART AND DRUG INTERACTIONS

Mary Bishop RPH, AAHIVEHIV/AIDS Clinical PharmacistUofL Healthcare Pharmacy

11/05/11

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

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?

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 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???

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

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

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

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 gondiiProphylaxis (CD4+ cell count <100): Bactrim DS 1 PO QD

Treatment: Sulfadiazine and Pyrimethamine + folinic acid

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)

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 anti-HTN 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

• 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