Antiretroviral Combinations

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Antiretroviral Combinations

• James A Zachary MDLSU Health Sciences CenterHIV
  Outpatient ClinicDecember 13, 2004
• http//HIVManagement.org

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Objectives

• Review rationale for combinations
• Review basis of protease inhibitor interactions
• Review specific combinations (mainly PI)
• Review what is not known
• Final recommendations

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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

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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)

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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

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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 gt saquinavir lopinavir indinavir gt
  amprenavir
• A flavinoid component which is peculiar to
  grapefruit (narangin or narangenin) blocks
  CYP4503A4 metabolism at the enzyme level

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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

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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

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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 protease
  inhibitors, 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.

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P-450inhibition P-450induction P-glyinhibition HRP 12inhibition
Increase PI Levels X X X
Decrease PI Levels X
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P450inhibition P450induction P-glyinhibition HRP 12inhibition
ritonavir X X X X
indinavir X
saquinavir X
nelfinavir X
lopinavir X X
amprenavir X
nevirapine X
efavirenz X X
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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

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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

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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

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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

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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

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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

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Nevirapine Effect on PIs
PI AUC Cmax Cmin IncreaseDose? BoostingEffective?
lopinavir with ritonavir 73 50 Yes Yes
indinavir 72 Yes Yes
fosamprenavir 67 No Yes
nelfinavir 68 Yes No
saquinavir 73 No Yes
atazanavir ? ? Theoretical
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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

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Efavirenz Effect on PIs
PI AUC Cmax Cmin IncreaseDose? BoostingEffective?
lopinavir /ritonavir 81 61 Yes Yes
indinavir 69 84 Yes Yes
fosamprenavir 64 No Yes
nelfinavir / nelfinavir metabolite 120/63 121/60 No Need No Need
saquinavir 38 50 No ?
atazanavir 79 No Yes
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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

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PI-PI interactions Lopinavir -
fosamprenavir/amprenavir

• Poorly tolerated
• Slightly decreased lopinavir and moderately
  decreased amprenavir levels
• Adding extra ritonavir further reduces
  amprenavir!!!

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PI-PI Interactions saquinavir - 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.

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PI-PI Interactions Lopinavir/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

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PI-PI Interactions Lopinavir/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

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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.

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Unknown Interactions

• Atazanavir - nevirapine
• Lopinavir/ritonavir - atazanavir

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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

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Patient 1

• 22 y/o man with AIDS CD4 122 VL gt 750k DMAC
• 122 lbs
• Cr 1.4
• Resistance testing M184V, 215, 219, 82, 84
• Proposed regimen
• Lopinavir/ritonavir
• Efavirenz
• Tenofovir
• Didanosine

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Patient 1

• 22 y/o man with AIDS CD4 122 VL gt 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

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Patient 1

• 22 y/o man with AIDS CD4 122 VL gt 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

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Patient 1

• 22 y/o man with AIDS CD4 122 VL gt 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

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Patient 1
Considerations
Drug Dosage
lopinavir/ritonavir
tenofovir
efavirenz
didanosine
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Patient 1
Considerations Low weight Renal failure Ccr 48 cc/min Drug interactions
Drug Dosage
lopinavir/ritonavir
tenofovir
efavirenz
didanosine
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Patient 1
Considerations Low weight Renal failure Ccr 48 cc/min Drug interactions
Drug Dosage
lopinavir/ritonavir 4 caps bid
tenofovir
efavirenz
didanosine
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Patient 1
Considerations Low weight Renal failure Ccr 48 cc/min Drug interactions
Drug Dosage
lopinavir/ritonavir 4 caps bid
tenofovir 300 mg every 48 hours
efavirenz
didanosine
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Patient 1
Considerations Low weight Renal failure Ccr 48 cc/min Drug interactions
Drug Dosage
lopinavir/ritonavir 4 caps bid
tenofovir 300 mg every 48 hours
efavirenz 600 mg daily
didanosine
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Patient 1
Considerations Low weight Renal failure Ccr 48 cc/min Drug interactions
Drug Dosage
lopinavir/ritonavir 4 caps bid
tenofovir 300 mg every 48 hours
efavirenz 600 mg daily
didanosine 100 125 mg daily?
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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