Antiretroviral Combinations

Antiretroviral Antiretroviral CombinationsCombinations

James A Zachary MDJames A Zachary MDLSU Health Sciences CenterLSU Health Sciences Center

HIV Outpatient ClinicHIV Outpatient ClinicDecember 13, 2004December 13, 2004

http://HIVManagement.orghttp://HIVManagement.org

ObjectivesObjectives

Review rationale for combinationsReview rationale for combinations Review basis of protease inhibitor Review basis of protease inhibitor

interactionsinteractions Review specific combinations Review specific combinations

(mainly PI)(mainly PI) Review what is not knownReview what is not known Final recommendationsFinal recommendations

Benefits of BoostingBenefits of Boosting

Improved adherenceImproved adherence Decrease pill burdenDecrease pill burden Decrease dosing frequencyDecrease dosing frequency Decrease meal dependenceDecrease meal dependence

Improve efficacyImprove efficacy Improved adherenceImproved adherence Improved levels of protease inhibitorsImproved levels of protease inhibitors

Levels out interindividual variationsLevels out interindividual variations Compensates for the effects of inducersCompensates for the effects of inducers

Problems of BoostingProblems of Boosting Multiple drug-drug interactionsMultiple drug-drug interactions Increased serum lipid & fat redistribution Increased serum lipid & fat redistribution

side effectsside effects Increased side effectsIncreased side effects

Abdominal painAbdominal pain DiarrheaDiarrhea NauseaNausea HepatitisHepatitis Perioral paresthesiaPerioral paresthesia

Increased number of prescribed medicationsIncreased number of prescribed medications Need to refrigerate medication (ritonavir)Need to refrigerate medication (ritonavir)

PharmacologyPharmacology

Protease inhibitors and NNRTIs are Protease inhibitors and NNRTIs are primarily metabolized via cytochrome primarily metabolized via cytochrome P-450 familyP-450 family of enzymes of enzymes

P-450 enzymesP-450 enzymes Primarily in liver but also in apical Primarily in liver but also in apical

enterocytesenterocytes Multiple metabolic pathways by which Multiple metabolic pathways by which

these drugs are metabolized, with the these drugs are metabolized, with the most significant being most significant being CYP3A4CYP3A4

P-450P-450

InhibitionInhibition Inhibition can lead to increases in drug Inhibition can lead to increases in drug

levels of agents that are normally levels of agents that are normally metabolized through CYP450metabolized through CYP450

Can occur after the first dose of an enzyme Can occur after the first dose of an enzyme inhibitorinhibitor

Ritonavir > saquinavir = lopinavir = Ritonavir > saquinavir = lopinavir = indinavir > amprenavirindinavir > amprenavir

A flavinoid component which is peculiar to A flavinoid component which is peculiar to grapefruitgrapefruit (narangin or narangenin) blocks (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level CYP4503A4 metabolism at the enzyme level

P-450P-450

InductionInduction Leads to a decrease in serum Leads to a decrease in serum

concentrations in drug levels with the concentrations in drug levels with the time frame for maximal induction time frame for maximal induction being about 2 weeksbeing about 2 weeks

Ritonavir, nelfinavir, and lopinavirRitonavir, nelfinavir, and lopinavir

P-450P-450

Mixed induction-inhibitionMixed induction-inhibition Complex drug Complex drug interactionsinteractions Difficult to predictDifficult to predict Changes over the first 2 week periodChanges over the first 2 week period Drugs can induce themselves and thus Drugs can induce themselves and thus

counter the inhibitory effects of counter the inhibitory effects of induction itselfinduction itself

Drug interaction studies necessaryDrug interaction studies necessary Ritonavir, lopinavirRitonavir, lopinavir

Other MechanismsOther Mechanisms P-glycoproteinP-glycoprotein

Transmembrane ATP-dependent, efflux membrane Transmembrane ATP-dependent, efflux membrane transport protein that is widely distributed in the transport protein that is widely distributed in the GI tract, liver, and kidneyGI tract, liver, and kidney

Absorption of the drugs, such as the Absorption of the drugs, such as the proteaseprotease inhibitorsinhibitors, may be decreased, leading to , may be decreased, leading to variations in bioavailabilityvariations in bioavailability

Inhibition of p-glycoprotein may increase Inhibition of p-glycoprotein may increase penetration/absorption penetration/absorption

Inhibited by ritonavir and probenecidInhibited by ritonavir and probenecid Multidrug resistance proteins 1 and 2Multidrug resistance proteins 1 and 2 Inhibition of these proteins increases Inhibition of these proteins increases

penetration of protease inhibitors into penetration of protease inhibitors into CNS, seminal fluid, etc.CNS, seminal fluid, etc.

P-450P-450inhibitiinhibiti

onon

P-450P-450inductiinducti

onon

P-glyP-glyinhibitiinhibiti

onon

HRP 1+2HRP 1+2inhibitioinhibitio

nn

Increase Increase PI LevelsPI Levels XX XX XXDecrease Decrease PI LevelsPI Levels XX

P450P450inhibitiinhibiti

onon

P450P450inductiinducti

onon

P-glyP-glyinhibitiinhibiti

onon

HRP 1+2HRP 1+2inhibitioinhibitio

nn

ritonavirritonavir XX XX XX XXindinavirindinavir XXsaquinavirsaquinavir XXnelfinavirnelfinavir XXlopinavirlopinavir XX XXamprenaviamprenavirr XXnevirapinnevirapinee XX

efavirenzefavirenz XX XX

Boosted SaquinavirBoosted Saquinavir

First boosted regimen employed: First boosted regimen employed: saquinavir hard gel caps (Invirase) saquinavir hard gel caps (Invirase) 400 mg + ritonavir 400 mg bid with 400 mg + ritonavir 400 mg bid with foodfood Higher levels of saquinavir than could be Higher levels of saquinavir than could be

achievedachieved Increased toxicity: GI upset, hepatitis, Increased toxicity: GI upset, hepatitis,

hyperlipidemia, fat redistributionhyperlipidemia, fat redistribution

Soft gel caps (Fortovase) better Soft gel caps (Fortovase) better absorbed but more GI upsetabsorbed but more GI upset

Boosted SaquinavirBoosted Saquinavir Saquinavir hard gel caps (Invirase)Saquinavir hard gel caps (Invirase)

Twice a dayTwice a day: SQV 5 x 200 mg + RTV 100 mg, : SQV 5 x 200 mg + RTV 100 mg, both bid taken together, optimally with foodboth bid taken together, optimally with food

Once a dayOnce a day: SQV 8x200 mg + RTV 100-200 : SQV 8x200 mg + RTV 100-200 mg, both once a day, optimally with foodmg, both once a day, optimally with food

Less GI upset, hepatitis, hyperlipidemiaLess GI upset, hepatitis, hyperlipidemia Decreases meal dependence, dosing frequency Decreases meal dependence, dosing frequency

and increases levels of SQV and increases levels of SQV Eliminates need to refrigerate soft gel capsEliminates need to refrigerate soft gel caps Can overcome decreased levels due to Can overcome decreased levels due to

nevirapine or efavirenz interactionsnevirapine or efavirenz interactions

Boosted IndinavirBoosted Indinavir Indinavir dosing normally Indinavir dosing normally q8hoursq8hours on on

an an empty stomachempty stomach RegimensRegimens

Indinavir 2 x 400 mg + ritonavir 100-200 bid Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without foodwith or without food

Indinavir 400 mg + ritonavir 200 mg bid Indinavir 400 mg + ritonavir 200 mg bid with or without foodwith or without food

Boosting decreases dosing frequency Boosting decreases dosing frequency and meal dependenceand meal dependence

Overcomes nevirapine or efavirenz Overcomes nevirapine or efavirenz problemsproblems

Boosted AtazanavirBoosted Atazanavir Atazanavir approved 2003Atazanavir approved 2003 Atazanavir levels decreased by tenofovir, Atazanavir levels decreased by tenofovir,

efavirenzefavirenz Unboosted regimen: atazanavir 2 x 200 mg Unboosted regimen: atazanavir 2 x 200 mg

caps q24hcaps q24h Boosted Regimen: atazanavir 2 x 150-200 mg Boosted Regimen: atazanavir 2 x 150-200 mg

once a day with food + 100 mg ritonavir once a once a day with food + 100 mg ritonavir once a dayday

Boosting increases incidence of hyperlipidemia and Boosting increases incidence of hyperlipidemia and possibly of jaundicepossibly of jaundice

Studies suggest that boosted atazanavir may be a Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonaviruseful salvage strategy similar to lopinavir/ritonavir

Boosted FosamprenavirBoosted Fosamprenavir Unboosted fosamprenavir 2 x 700 mg bidUnboosted fosamprenavir 2 x 700 mg bid Boosted regimens:Boosted regimens:

Fosamprenavir 1 x 700 mg + ritonavir 100 mg, Fosamprenavir 1 x 700 mg + ritonavir 100 mg, both bidboth bid

Fosamprenavir 2 x 700 mg + ritonavir 2 x 100 mg, Fosamprenavir 2 x 700 mg + ritonavir 2 x 100 mg, both once a day – recommended for naïve patients both once a day – recommended for naïve patients onlyonly

Probably best used as first line boosted PIProbably best used as first line boosted PI May be able to overcome some PI resistanceMay be able to overcome some PI resistance Well toleratedWell tolerated Increased hyperlipidemia with boosted regimenIncreased hyperlipidemia with boosted regimen May overcome nevirapine and efavirenz May overcome nevirapine and efavirenz

interactionsinteractions

PI – NNRTI InteractionsPI – NNRTI Interactions Nevirapine: a P-450 inducerNevirapine: a P-450 inducer

Decreases lopinavir/ritonavir levels (27% Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin)AUC, 50% dec Cmin)

Decreases indinavir levels (28% dec AUC)Decreases indinavir levels (28% dec AUC) Decreases fosamprenavir levels (33% dec Decreases fosamprenavir levels (33% dec

AUC)AUC) Decreases nelfinavir levels (32% dec Cmin)Decreases nelfinavir levels (32% dec Cmin) Decreases saquinavir levels (27% dec AUC)Decreases saquinavir levels (27% dec AUC) Unknown: atazanavirUnknown: atazanavir Compensate for P-450 inductionCompensate for P-450 induction

Increase dosage or boost: indinavir, Increase dosage or boost: indinavir, lopinavir/ritonavirlopinavir/ritonavir

Increase nelfinavirIncrease nelfinavir Boost fosamprenavir, saquinavirBoost fosamprenavir, saquinavir

↓↓

Nevirapine Effect on PIsNevirapine Effect on PIs

PIPI AUCAUC CmaxCmax CminCmin IncreaseIncreaseDose?Dose?

BoostingBoostingEffective?Effective?

lopinavir lopinavir withwith

ritonavirritonavir73%73% 50%50% YesYes YesYes

indinavirindinavir 72%72% YesYes YesYesfosamprenafosamprenavirvir 67%67% NoNo YesYes

nelfinavirnelfinavir 68%68% YesYes NoNosaquinavirsaquinavir 73%73% NoNo YesYes

atazanaviratazanavir ?? ?? TheoreticTheoreticalal

PI – NNRTI InteractionsPI – NNRTI Interactions Efavirenz: a P-450 inducer/inhibitorEfavirenz: a P-450 inducer/inhibitor

Decreases lopinavir/ritonavir levels (19% dec Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin)AUC, 39% dec Cmin)

Decreases indinavir levels (31% AUC, 16% dec Decreases indinavir levels (31% AUC, 16% dec Cmax)Cmax)

Decreases fosamprenavir levels (36% dec Decreases fosamprenavir levels (36% dec AUC)AUC)

No significant nelfinavir interaction (20% inc No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite)AUC, 37% dec in AUC metabolite)

Decreases saquinavir levels (62% dec AUC, 50 Decreases saquinavir levels (62% dec AUC, 50 dec Cmax)dec Cmax)

Decreases atazanavir levels (21% dec AUC)Decreases atazanavir levels (21% dec AUC) Compensate for P-450 induction/inhibitionCompensate for P-450 induction/inhibition

Increase dosage or boost: indinavir, Increase dosage or boost: indinavir, lopinavir/ritonavirlopinavir/ritonavir

No change in nelfinavirNo change in nelfinavir Boost fosamprenavir, saquinavir?, atazanavirBoost fosamprenavir, saquinavir?, atazanavir

Efavirenz Effect on PIsEfavirenz Effect on PIs

PIPI AUCAUC CmaxCmax CminCmin IncreaseIncreaseDose?Dose?

BoostingBoostingEffective?Effective?

lopinavir /lopinavir /ritonavirritonavir 81%81% 61%61% YesYes YesYes

indinavirindinavir 69%69% 84%84% YesYes YesYesfosamprenafosamprenavirvir 64%64% NoNo YesYes

nelfinavir /nelfinavir /

nelfinavir nelfinavir metabolitemetabolite

120%120%//

63%63%

121%/121%/60%60%

No No

NeedNeedNo No

NeedNeed

saquinavirsaquinavir 38%38% 50%50% NoNo ??atazanaviratazanavir 79%79% NoNo YesYes

Tenofovir InteractionsTenofovir Interactions Nucleotide antiretroviralNucleotide antiretroviral AtazanavirAtazanavir

Decreases atazanavir levelsDecreases atazanavir levels Levels of tenofovir increased by atazanavirLevels of tenofovir increased by atazanavir Compensate by using boosted atazanavir and Compensate by using boosted atazanavir and

observe for tenofovir toxicityobserve for tenofovir toxicity Lopinavir/ritonavirLopinavir/ritonavir

Levels of tenofovir increased: observe for Levels of tenofovir increased: observe for toxicitytoxicity

DidanosineDidanosine Levels of didanosine increased (144-160% AUC)Levels of didanosine increased (144-160% AUC) Compensate by decreasing dose of didanosineCompensate by decreasing dose of didanosine

PI-PI interactionsPI-PI interactions Lopinavir - fosamprenavir/amprenavirLopinavir - fosamprenavir/amprenavir

Poorly toleratedPoorly tolerated Slightly decreased lopinavir and Slightly decreased lopinavir and

moderately decreased moderately decreased amprenavir levelsamprenavir levels

Adding extra ritonavir further Adding extra ritonavir further reduces amprenavir!!!reduces amprenavir!!!

PI-PI InteractionsPI-PI Interactions saquinavir - atazanavir - ritonavirsaquinavir - atazanavir - ritonavir

Normal atazanavir levelsNormal atazanavir levels Boosted the trough levels of saquinavir Boosted the trough levels of saquinavir

112% over baseline, peak levels by 112% over baseline, peak levels by 42%, area under the curve by 60% and 42%, area under the curve by 60% and extended the saquinavir half-life by 17%extended the saquinavir half-life by 17%

Atazanavir reduced the trough levels of Atazanavir reduced the trough levels of ritonavir by 28% and the half-life by ritonavir by 28% and the half-life by 17% (this latter result was not 17% (this latter result was not statistically significant); but peak levels statistically significant); but peak levels were boosted by 58% and AUC by 41%. were boosted by 58% and AUC by 41%.

PI-PI InteractionsPI-PI Interactions Lopinavir/ritonavir – saquinavirLopinavir/ritonavir – saquinavir

Synergistic against viruses resistant Synergistic against viruses resistant to LPV but still sensitive to SQVto LPV but still sensitive to SQV

Limited data on interactionsLimited data on interactions DosingDosing

Standard lopinavir/ritonavir Standard lopinavir/ritonavir 400/100 bid400/100 bid

Invirase 800-1000 bidInvirase 800-1000 bid

PI-PI InteractionsPI-PI Interactions Lopinavir/ritonavir – indinavirLopinavir/ritonavir – indinavir

Indinavir (600 mg twice daily) when Indinavir (600 mg twice daily) when coadministered with Kaletra coadministered with Kaletra (400/100 mg twice daily) may (400/100 mg twice daily) may produce a similar AUC and higher produce a similar AUC and higher Cmin relative to the established Cmin relative to the established clinical dosing regimenclinical dosing regimen

11 subjects11 subjects

PI-PI InteractionsPI-PI Interactionsindinavir - saquinavirindinavir - saquinavir

Coadministration of indinavir (800 mg three Coadministration of indinavir (800 mg three times daily) and a single dose of the soft gel times daily) and a single dose of the soft gel formulation of saquinavir (800 or 1200 mg formulation of saquinavir (800 or 1200 mg single dose) single dose)

N = 6N = 6 800 mg saquinavir dose showed a 620% 800 mg saquinavir dose showed a 620%

increase in AUC and a 551% increase in Cmax. increase in AUC and a 551% increase in Cmax. 1200 mg saquinavir dose showed a 364% 1200 mg saquinavir dose showed a 364%

increase in AUC and a 299% increase in Cmax. increase in AUC and a 299% increase in Cmax. There were no apparent clinically relevant There were no apparent clinically relevant

changes to indinavir pharmacokinetics when changes to indinavir pharmacokinetics when coadministered with the soft gel formulation of coadministered with the soft gel formulation of saquinavir. saquinavir.

Unknown InteractionsUnknown Interactions

Atazanavir - nevirapineAtazanavir - nevirapineLopinavir/ritonavir - Lopinavir/ritonavir - atazanaviratazanavir

Adverse PI InteractionsAdverse PI InteractionsMany Overcome By Boosting Many Overcome By Boosting

Lopinavir + amprenavir or Lopinavir + amprenavir or fosamprenavirfosamprenavir

Saquinavir + nevirapine or efavirenzSaquinavir + nevirapine or efavirenz Atazanavir + tenofovir Atazanavir + tenofovir Atazanavir + efavirenz Atazanavir + efavirenz Atazanavir + efavirenz + tenofovir Atazanavir + efavirenz + tenofovir Atazanavir + nevirapine Atazanavir + nevirapine Indinavir + nevirapine or efavirenz Indinavir + nevirapine or efavirenz Fosamprenavir + nevirapine or efavirenzFosamprenavir + nevirapine or efavirenz

Patient 1Patient 1

22 y/o man with AIDS CD4 122 VL > 750k 22 y/o man with AIDS CD4 122 VL > 750k DMACDMAC

122 lbs122 lbs Cr 1.4Cr 1.4 Resistance testing: M184V, 215, 219, 82, Resistance testing: M184V, 215, 219, 82,

8484 Proposed regimenProposed regimen

Lopinavir/ritonavirLopinavir/ritonavir EfavirenzEfavirenz Tenofovir Tenofovir DidanosineDidanosine

Patient 1Patient 1

22 y/o man with AIDS CD4 122 VL > 750k 22 y/o man with AIDS CD4 122 VL > 750k DMACDMAC

122 lbs, 69 in122 lbs, 69 in Nephropathy Cr 1.9Nephropathy Cr 1.9 Resistance testing: M184V, 215, 219, 82, 84Resistance testing: M184V, 215, 219, 82, 84 Proposed regimenProposed regimen

Lopinavir/ritonavir: levels decreased by Lopinavir/ritonavir: levels decreased by efavirenzefavirenz

EfavirenzEfavirenz Tenofovir Tenofovir DidanosineDidanosine

Patient 1Patient 1

22 y/o man with AIDS CD4 122 VL > 750k DMAC22 y/o man with AIDS CD4 122 VL > 750k DMAC 122 lbs122 lbs Cr 1.4Cr 1.4 Resistance testing: M184V, 215, 219, 82, 84Resistance testing: M184V, 215, 219, 82, 84 Proposed regimenProposed regimen

Lopinavir/ritonavirLopinavir/ritonavir EfavirenzEfavirenz Tenofovir: levels increased by renal failure and Tenofovir: levels increased by renal failure and

lopinavir/rtvlopinavir/rtv DidanosineDidanosine

Patient 1Patient 1 22 y/o man with AIDS CD4 122 VL > 750k 22 y/o man with AIDS CD4 122 VL > 750k

DMACDMAC 122 lbs122 lbs Cr 1.6Cr 1.6 Resistance testing: M184V, 215, 219, 82, 84Resistance testing: M184V, 215, 219, 82, 84 Proposed regimenProposed regimen

Lopinavir/ritonavirLopinavir/ritonavir EfavirenzEfavirenz Tenofovir Tenofovir Didanosine: levels increased by low weight, Didanosine: levels increased by low weight,

renal failure, and tenofovirrenal failure, and tenofovir

Patient 1Patient 1

ConsiderationsConsiderations

Drug Drug DosageDosagelopinavir/lopinavir/ritonavirritonavir

tenofovirtenofovir

efavirenzefavirenz

didanosinedidanosine

Patient 1Patient 1

ConsiderationsConsiderationsLow weightLow weight

Renal failure [Ccr= 48 cc/min]Renal failure [Ccr= 48 cc/min]

Drug interactionsDrug interactions

Drug Drug DosageDosagelopinavir/lopinavir/ritonavirritonavir

tenofovirtenofovir

efavirenzefavirenz


Patient 1Patient 1




Drug Drug DosageDosagelopinavir/lopinavir/ritonavirritonavir 4 caps bid4 caps bid

tenofovirtenofovir

efavirenzefavirenz


Patient 1Patient 1





tenofovirtenofovir 300 mg every 48 hours*300 mg every 48 hours*

efavirenzefavirenz


Patient 1Patient 1






efavirenzefavirenz 600 mg daily600 mg daily


Patient 1Patient 1






efavirenzefavirenz 600 mg daily600 mg daily

didanosinedidanosine 100 – 125 mg daily?100 – 125 mg daily?

Final RecommendationsFinal Recommendations

Look up all interactions using a Look up all interactions using a computer or PDAcomputer or PDA

Avoid using drugs together which Avoid using drugs together which have not been studiedhave not been studied

Pay close attention to body weight, Pay close attention to body weight, hepatic and renal impairmenthepatic and renal impairment

Follow liver enzymes and renal Follow liver enzymes and renal function closelyfunction closely

Documents

Antiretroviral Combinations