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Antiretroviral Combinations. James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic December 13, 2004 http://HIVManagement.org. Objectives. Review rationale for combinations Review basis of protease inhibitor interactions Review specific combinations (mainly PI)

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antiretroviral combinations

Antiretroviral Combinations

James A Zachary MDLSU Health Sciences CenterHIV Outpatient ClinicDecember 13, 2004

http://HIVManagement.org

objectives
Objectives
  • Review rationale for combinations
  • Review basis of protease inhibitor interactions
  • Review specific combinations (mainly PI)
  • Review what is not known
  • Final recommendations
benefits of boosting
Benefits of Boosting
  • Improved adherence
    • Decrease pill burden
    • Decrease dosing frequency
    • Decrease meal dependence
  • Improve efficacy
    • Improved adherence
    • Improved levels of protease inhibitors
      • Levels out interindividual variations
      • Compensates for the effects of inducers
problems of boosting
Problems of Boosting
  • Multiple drug-drug interactions
  • Increased serum lipid & fat redistribution side effects
  • Increased side effects
    • Abdominal pain
    • Diarrhea
    • Nausea
    • Hepatitis
    • Perioral paresthesia
  • Increased number of prescribed medications
  • Need to refrigerate medication (ritonavir)
pharmacology
Pharmacology
  • Protease inhibitors and NNRTIs are primarily metabolized via cytochrome P-450 family of enzymes
  • P-450 enzymes
    • Primarily in liver but also in apical enterocytes
    • Multiple metabolic pathways by which these drugs are metabolized, with the most significant being CYP3A4
p 450
P-450
  • Inhibition
    • Inhibition can lead to increases in drug levels of agents that are normally metabolized through CYP450
    • Can occur after the first dose of an enzyme inhibitor
    • Ritonavir > saquinavir = lopinavir = indinavir > amprenavir
    • A flavinoid component which is peculiar to grapefruit (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level
p 4501
P-450
  • Induction
    • Leads to a decrease in serum concentrations in drug levels with the time frame for maximal induction being about 2 weeks
    • Ritonavir, nelfinavir, and lopinavir
p 4502
P-450
  • Mixed induction-inhibition
    • Complex drug interactions
    • Difficult to predict
    • Changes over the first 2 week period
    • Drugs can induce themselves and thus counter the inhibitory effects of induction itself
    • Drug interaction studies necessary
    • Ritonavir, lopinavir
other mechanisms
Other Mechanisms
  • P-glycoprotein
    • Transmembrane ATP-dependent, efflux membrane transport protein that is widely distributed in the GI tract, liver, and kidney
    • Absorption of the drugs, such as the proteaseinhibitors, may be decreased, leading to variations in bioavailability
    • Inhibition of p-glycoprotein may increase penetration/absorption
    • Inhibited by ritonavir and probenecid
  • Multidrug resistance proteins 1 and 2
  • Inhibition of these proteins increases penetration of protease inhibitors into CNS, seminal fluid, etc.
boosted saquinavir
Boosted Saquinavir
  • First boosted regimen employed: saquinavir hard gel caps (Invirase) 400 mg + ritonavir 400 mg bid with food
    • Higher levels of saquinavir than could be achieved
    • Increased toxicity: GI upset, hepatitis, hyperlipidemia, fat redistribution
  • Soft gel caps (Fortovase) better absorbed but more GI upset
boosted saquinavir1
Boosted Saquinavir
  • Saquinavir hard gel caps (Invirase)
    • Twice a day: SQV 5 x 200 mg + RTV 100 mg, both bid taken together, optimally with food
    • Once a day: SQV 8x200 mg + RTV 100-200 mg, both once a day, optimally with food
    • Less GI upset, hepatitis, hyperlipidemia
    • Decreases meal dependence, dosing frequency and increases levels of SQV
    • Eliminates need to refrigerate soft gel caps
    • Can overcome decreased levels due to nevirapine or efavirenz interactions
boosted indinavir
Boosted Indinavir
  • Indinavir dosing normally q8hours on an empty stomach
  • Regimens
    • Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without food
    • Indinavir 400 mg + ritonavir 200 mg bid with or without food
  • Boosting decreases dosing frequency and meal dependence
  • Overcomes nevirapine or efavirenz problems
boosted atazanavir
Boosted Atazanavir
  • Atazanavir approved 2003
  • Atazanavir levels decreased by tenofovir, efavirenz
  • Unboosted regimen: atazanavir 2 x 200 mg caps q24h
  • Boosted Regimen: atazanavir 2 x 150-200 mg once a day with food + 100 mg ritonavir once a day
  • Boosting increases incidence of hyperlipidemia and possibly of jaundice
  • Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonavir
boosted fosamprenavir
Boosted Fosamprenavir
  • Unboosted fosamprenavir 2 x 700 mg bid
  • Boosted regimens:
    • Fosamprenavir 1 x 700 mg + ritonavir 100 mg, both bid
    • Fosamprenavir 2 x 700 mg + ritonavir 2 x 100 mg, both once a day – recommended for naïve patients only
  • Probably best used as first line boosted PI
  • May be able to overcome some PI resistance
  • Well tolerated
  • Increased hyperlipidemia with boosted regimen
  • May overcome nevirapine and efavirenz interactions
pi nnrti interactions
PI – NNRTI Interactions

  • Nevirapine: a P-450 inducer
    • Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin)
    • Decreases indinavir levels (28% dec AUC)
    • Decreases fosamprenavir levels (33% dec AUC)
    • Decreases nelfinavir levels (32% dec Cmin)
    • Decreases saquinavir levels (27% dec AUC)
    • Unknown: atazanavir
    • Compensate for P-450 induction
      • Increase dosage or boost: indinavir, lopinavir/ritonavir
      • Increase nelfinavir
      • Boost fosamprenavir, saquinavir
pi nnrti interactions1
PI – NNRTI Interactions
  • Efavirenz: a P-450 inducer/inhibitor
    • Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin)
    • Decreases indinavir levels (31% AUC, 16% dec Cmax)
    • Decreases fosamprenavir levels (36% dec AUC)
    • No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite)
    • Decreases saquinavir levels (62% dec AUC, 50 dec Cmax)
    • Decreases atazanavir levels (21% dec AUC)
    • Compensate for P-450 induction/inhibition
      • Increase dosage or boost: indinavir, lopinavir/ritonavir
      • No change in nelfinavir
      • Boost fosamprenavir, saquinavir?, atazanavir
tenofovir interactions
Tenofovir Interactions
  • Nucleotide antiretroviral
  • Atazanavir
    • Decreases atazanavir levels
    • Levels of tenofovir increased by atazanavir
    • Compensate by using boosted atazanavir and observe for tenofovir toxicity
  • Lopinavir/ritonavir
    • Levels of tenofovir increased: observe for toxicity
  • Didanosine
    • Levels of didanosine increased (144-160% AUC)
    • Compensate by decreasing dose of didanosine
pi pi interactions lopinavir fosamprenavir amprenavir
PI-PI interactionsLopinavir - fosamprenavir/amprenavir
  • Poorly tolerated
  • Slightly decreased lopinavir and moderately decreased amprenavir levels
  • Adding extra ritonavir further reduces amprenavir!!!
pi pi interactions saquinavir atazanavir ritonavir
PI-PI Interactionssaquinavir - atazanavir - ritonavir
  • Normal atazanavir levels
  • Boosted the trough levels of saquinavir 112% over baseline, peak levels by 42%, area under the curve by 60% and extended the saquinavir half-life by 17%
  • Atazanavir reduced the trough levels of ritonavir by 28% and the half-life by 17% (this latter result was not statistically significant); but peak levels were boosted by 58% and AUC by 41%.
pi pi interactions lopinavir ritonavir saquinavir
PI-PI InteractionsLopinavir/ritonavir – saquinavir
  • Synergistic against viruses resistant to LPV but still sensitive to SQV
  • Limited data on interactions
  • Dosing
      • Standard lopinavir/ritonavir 400/100 bid
      • Invirase 800-1000 bid
pi pi interactions lopinavir ritonavir indinavir
PI-PI InteractionsLopinavir/ritonavir – indinavir
  • Indinavir (600 mg twice daily) when coadministered with Kaletra (400/100 mg twice daily) may produce a similar AUC and higher Cmin relative to the established clinical dosing regimen
  • 11 subjects
pi pi interactions indinavir saquinavir
PI-PI Interactionsindinavir - saquinavir
  • Coadministration of indinavir (800 mg three times daily) and a single dose of the soft gel formulation of saquinavir (800 or 1200 mg single dose)
  • N = 6
  • 800 mg saquinavir dose showed a 620% increase in AUC and a 551% increase in Cmax.
  • 1200 mg saquinavir dose showed a 364% increase in AUC and a 299% increase in Cmax.
  • There were no apparent clinically relevant changes to indinavir pharmacokinetics when coadministered with the soft gel formulation of saquinavir.
unknown interactions
Unknown Interactions
  • Atazanavir - nevirapine
  • Lopinavir/ritonavir - atazanavir
adverse pi interactions many overcome by boosting
Adverse PI InteractionsMany Overcome By Boosting
  • Lopinavir + amprenavir or fosamprenavir
  • Saquinavir + nevirapine or efavirenz
  • Atazanavir + tenofovir
  • Atazanavir + efavirenz
  • Atazanavir + efavirenz + tenofovir
  • Atazanavir + nevirapine
  • Indinavir + nevirapine or efavirenz
  • Fosamprenavir + nevirapine or efavirenz
patient 1
Patient 1
  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC
  • 122 lbs
  • Cr 1.4
  • Resistance testing: M184V, 215, 219, 82, 84
  • Proposed regimen
    • Lopinavir/ritonavir
    • Efavirenz
    • Tenofovir
    • Didanosine
patient 11
Patient 1
  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC
  • 122 lbs, 69 in
  • Nephropathy Cr 1.9
  • Resistance testing: M184V, 215, 219, 82, 84
  • Proposed regimen
    • Lopinavir/ritonavir: levels decreased by efavirenz
    • Efavirenz
    • Tenofovir
    • Didanosine
patient 12
Patient 1
  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC
  • 122 lbs
  • Cr 1.4
  • Resistance testing: M184V, 215, 219, 82, 84
  • Proposed regimen
    • Lopinavir/ritonavir
    • Efavirenz
    • Tenofovir: levels increased by renal failure and lopinavir/rtv
    • Didanosine
patient 13
Patient 1
  • 22 y/o man with AIDS CD4 122 VL > 750k DMAC
  • 122 lbs
  • Cr 1.6
  • Resistance testing: M184V, 215, 219, 82, 84
  • Proposed regimen
    • Lopinavir/ritonavir
    • Efavirenz
    • Tenofovir
    • Didanosine: levels increased by low weight, renal failure, and tenofovir
final recommendations
Final Recommendations
  • Look up all interactions using a computer or PDA
  • Avoid using drugs together which have not been studied
  • Pay close attention to body weight, hepatic and renal impairment
  • Follow liver enzymes and renal function closely
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