1. Antiretroviral Combinations James A Zachary MD LSU Health Sciences Center HIV Outpatient Clinic December 13, 2004 http://HIVManagement.org

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

3. Benefits of Boosting Improved adherence Improved adherence Decrease pill burden Decrease pill burden Decrease dosing frequency Decrease dosing frequency Decrease meal dependence Decrease meal dependence Improve efficacy Improve efficacy Improved adherence Improved adherence Improved levels of protease inhibitors Improved levels of protease inhibitors Levels out interindividual variations Levels out interindividual variations Compensates for the effects of inducers Compensates for the effects of inducers

4. Problems of Boosting Multiple drug-drug interactions Multiple drug-drug interactions Increased serum lipid & fat redistribution side effects Increased serum lipid & fat redistribution side effects Increased side effects Increased side effects Abdominal pain Abdominal pain Diarrhea Diarrhea Nausea Nausea Hepatitis Hepatitis Perioral paresthesia Perioral paresthesia Increased number of prescribed medications Increased number of prescribed medications Need to refrigerate medication (ritonavir) Need to refrigerate medication (ritonavir)

5. Pharmacology Protease inhibitors and NNRTIs are primarily metabolized via cytochrome P-450 family of enzymes Protease inhibitors and NNRTIs are primarily metabolized via cytochrome P-450 family of enzymes P-450 enzymes P-450 enzymes Primarily in liver but also in apical enterocytes Primarily in liver but also in apical enterocytes Multiple metabolic pathways by which these drugs are metabolized, with the most significant being CYP3A4 Multiple metabolic pathways by which these drugs are metabolized, with the most significant being CYP3A4

8. P-450 Inhibition Inhibition Inhibition can lead to increases in drug levels of agents that are normally metabolized through CYP450 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 Can occur after the first dose of an enzyme inhibitor Ritonavir > saquinavir = lopinavir = indinavir > amprenavir Ritonavir > saquinavir = lopinavir = indinavir > amprenavir A flavinoid component which is peculiar to grapefruit (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level A flavinoid component which is peculiar to grapefruit (narangin or narangenin) blocks CYP4503A4 metabolism at the enzyme level

9. P-450 Induction Induction Leads to a decrease in serum concentrations in drug levels with the time frame for maximal induction being about 2 weeks 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 Ritonavir, nelfinavir, and lopinavir

10. P-450 Mixed induction-inhibition Mixed induction-inhibition Complex drug interactions Complex drug interactions Difficult to predict Difficult to predict Changes over the first 2 week period Changes over the first 2 week period Drugs can induce themselves and thus counter the inhibitory effects of induction itself Drugs can induce themselves and thus counter the inhibitory effects of induction itself Drug interaction studies necessary Drug interaction studies necessary Ritonavir, lopinavir Ritonavir, lopinavir

11. Other Mechanisms P-glycoprotein P-glycoprotein Transmembrane ATP-dependent, efflux membrane transport protein that is widely distributed in the GI tract, liver, and kidney 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 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 Inhibition of p-glycoprotein may increase penetration/absorption Inhibited by ritonavir and probenecid Inhibited by ritonavir and probenecid Multidrug resistance proteins 1 and 2 Multidrug resistance proteins 1 and 2 Inhibition of these proteins increases penetration of protease inhibitors into CNS, seminal fluid, etc. Inhibition of these proteins increases penetration of protease inhibitors into CNS, seminal fluid, etc.

12. P-450 inhibition P-450 induction P-gly inhibition HRP 1+2 inhibition Increase PI Levels XXX Decrease PI Levels X

13. P450 inhibition P450 induction P-gly inhibition HRP 1+2 inhibition ritonavirXXXX indinavirX saquinavirX nelfinavirX lopinavirXX amprenavirX nevirapineX efavirenzXX

15. Boosted Saquinavir First boosted regimen employed: saquinavir hard gel caps (Invirase) 400 mg + ritonavir 400 mg bid with food 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 Higher levels of saquinavir than could be achieved Increased toxicity: GI upset, hepatitis, hyperlipidemia, fat redistribution Increased toxicity: GI upset, hepatitis, hyperlipidemia, fat redistribution Soft gel caps (Fortovase) better absorbed but more GI upset Soft gel caps (Fortovase) better absorbed but more GI upset

16. Boosted Saquinavir Saquinavir hard gel caps (Invirase) Saquinavir hard gel caps (Invirase) Twice a day: SQV 5 x 200 mg + RTV 100 mg, both bid taken together, optimally with food 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 Once a day: SQV 8x200 mg + RTV 100-200 mg, both once a day, optimally with food Less GI upset, hepatitis, hyperlipidemia Less GI upset, hepatitis, hyperlipidemia Decreases meal dependence, dosing frequency and increases levels of SQV Decreases meal dependence, dosing frequency and increases levels of SQV Eliminates need to refrigerate soft gel caps Eliminates need to refrigerate soft gel caps Can overcome decreased levels due to nevirapine or efavirenz interactions Can overcome decreased levels due to nevirapine or efavirenz interactions

17. Boosted Indinavir Indinavir dosing normally q8hours on an empty stomach Indinavir dosing normally q8hours on an empty stomach Regimens Regimens Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without food Indinavir 2 x 400 mg + ritonavir 100-200 bid with or without food Indinavir 400 mg + ritonavir 200 mg bid with or without food Indinavir 400 mg + ritonavir 200 mg bid with or without food Boosting decreases dosing frequency and meal dependence Boosting decreases dosing frequency and meal dependence Overcomes nevirapine or efavirenz problems Overcomes nevirapine or efavirenz problems

18. Boosted Atazanavir Atazanavir approved 2003 Atazanavir approved 2003 Atazanavir levels decreased by tenofovir, efavirenz Atazanavir levels decreased by tenofovir, efavirenz Unboosted regimen: atazanavir 2 x 200 mg caps q24h 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 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 Boosting increases incidence of hyperlipidemia and possibly of jaundice Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonavir Studies suggest that boosted atazanavir may be a useful salvage strategy similar to lopinavir/ritonavir

19. Boosted Fosamprenavir Unboosted fosamprenavir 2 x 700 mg bid Unboosted fosamprenavir 2 x 700 mg bid Boosted regimens: Boosted regimens: Fosamprenavir 1 x 700 mg + ritonavir 100 mg, both bid 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 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 Probably best used as first line boosted PI May be able to overcome some PI resistance May be able to overcome some PI resistance Well tolerated Well tolerated Increased hyperlipidemia with boosted regimen Increased hyperlipidemia with boosted regimen May overcome nevirapine and efavirenz interactions May overcome nevirapine and efavirenz interactions

20. PI – NNRTI Interactions Nevirapine: a P-450 inducer Nevirapine: a P-450 inducer Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin) Decreases lopinavir/ritonavir levels (27% AUC, 50% dec Cmin) Decreases indinavir levels (28% dec AUC) Decreases indinavir levels (28% dec AUC) Decreases fosamprenavir levels (33% dec AUC) Decreases fosamprenavir levels (33% dec 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: atazanavir Unknown: atazanavir Compensate for P-450 induction Compensate for P-450 induction Increase dosage or boost: indinavir, lopinavir/ritonavir Increase dosage or boost: indinavir, lopinavir/ritonavir Increase nelfinavir Increase nelfinavir Boost fosamprenavir, saquinavir Boost fosamprenavir, saquinavir ↓

21. Nevirapine Effect on PIs PIAUCCmaxCmin Increase Dose? Boosting Effective? lopinavir with ritonavir73%50%YesYes indinavir72%YesYes fosamprenavir67%NoYes nelfinavir68%YesNo saquinavir73%NoYes atazanavir??Theoretical

22. PI – NNRTI Interactions Efavirenz: a P-450 inducer/inhibitor Efavirenz: a P-450 inducer/inhibitor Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin) Decreases lopinavir/ritonavir levels (19% dec AUC, 39% dec Cmin) Decreases indinavir levels (31% AUC, 16% dec Cmax) Decreases indinavir levels (31% AUC, 16% dec Cmax) Decreases fosamprenavir levels (36% dec AUC) Decreases fosamprenavir levels (36% dec AUC) No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite) No significant nelfinavir interaction (20% inc AUC, 37% dec in AUC metabolite) Decreases saquinavir levels (62% dec AUC, 50 dec Cmax) Decreases saquinavir levels (62% dec AUC, 50 dec Cmax) Decreases atazanavir levels (21% dec AUC) Decreases atazanavir levels (21% dec AUC) Compensate for P-450 induction/inhibition Compensate for P-450 induction/inhibition Increase dosage or boost: indinavir, lopinavir/ritonavir Increase dosage or boost: indinavir, lopinavir/ritonavir No change in nelfinavir No change in nelfinavir Boost fosamprenavir, saquinavir?, atazanavir Boost fosamprenavir, saquinavir?, atazanavir

23. Efavirenz Effect on PIs PIAUCCmaxCmin Increase Dose? Boosting Effective? lopinavir / ritonavir 81%61%YesYes indinavir69%84%YesYes fosamprenavir64%NoYes nelfinavir / nelfinavir metabolite 120%/ 63% 121%/ 60% NoNeedNoNeed saquinavir38%50%No? atazanavir79%NoYes

24. Tenofovir Interactions Nucleotide antiretroviral Nucleotide antiretroviral Atazanavir Atazanavir Decreases atazanavir levels Decreases atazanavir levels Levels of tenofovir increased by atazanavir Levels of tenofovir increased by atazanavir Compensate by using boosted atazanavir and observe for tenofovir toxicity Compensate by using boosted atazanavir and observe for tenofovir toxicity Lopinavir/ritonavir Lopinavir/ritonavir Levels of tenofovir increased: observe for toxicity Levels of tenofovir increased: observe for toxicity Didanosine Didanosine Levels of didanosine increased (144-160% AUC) Levels of didanosine increased (144-160% AUC) Compensate by decreasing dose of didanosine Compensate by decreasing dose of didanosine

25. PI-PI interactions Lopinavir - fosamprenavir/amprenavir Poorly tolerated Poorly tolerated Slightly decreased lopinavir and moderately decreased amprenavir levels Slightly decreased lopinavir and moderately decreased amprenavir levels Adding extra ritonavir further reduces amprenavir!!! Adding extra ritonavir further reduces amprenavir!!!

26. PI-PI Interactions saquinavir - atazanavir - ritonavir Normal atazanavir levels 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% 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%. 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%.

27. PI-PI Interactions Lopinavir/ritonavir – saquinavir Synergistic against viruses resistant to LPV but still sensitive to SQV Synergistic against viruses resistant to LPV but still sensitive to SQV Limited data on interactions Limited data on interactions Dosing Dosing Standard lopinavir/ritonavir 400/100 bid Standard lopinavir/ritonavir 400/100 bid Invirase 800-1000 bid Invirase 800-1000 bid

28. 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 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 11 subjects

29. PI-PI Interactions indinavir - 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) 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 N = 6 800 mg saquinavir dose showed a 620% increase in AUC and a 551% increase in Cmax. 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. 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. There were no apparent clinically relevant changes to indinavir pharmacokinetics when coadministered with the soft gel formulation of saquinavir.

30. Unknown Interactions Atazanavir - nevirapine Atazanavir - nevirapine Lopinavir/ritonavir - atazanavir Lopinavir/ritonavir - atazanavir

31. Adverse PI Interactions Many Overcome By Boosting Lopinavir + amprenavir or fosamprenavir Lopinavir + amprenavir or fosamprenavir Saquinavir + nevirapine or efavirenz Saquinavir + 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 efavirenz Fosamprenavir + nevirapine or efavirenz

32. Patient 1 22 y/o man with AIDS CD4 122 VL > 750k DMAC 22 y/o man with AIDS CD4 122 VL > 750k DMAC 122 lbs 122 lbs Cr 1.4 Cr 1.4 Resistance testing: M184V, 215, 219, 82, 84 Resistance testing: M184V, 215, 219, 82, 84 Proposed regimen Proposed regimen Lopinavir/ritonavir Lopinavir/ritonavir Efavirenz Efavirenz Tenofovir Tenofovir Didanosine Didanosine

33. Patient 1 22 y/o man with AIDS CD4 122 VL > 750k DMAC 22 y/o man with AIDS CD4 122 VL > 750k DMAC 122 lbs, 69 in 122 lbs, 69 in Nephropathy Cr 1.9 Nephropathy Cr 1.9 Resistance testing: M184V, 215, 219, 82, 84 Resistance testing: M184V, 215, 219, 82, 84 Proposed regimen Proposed regimen Lopinavir/ritonavir: levels decreased by efavirenz Lopinavir/ritonavir: levels decreased by efavirenz Efavirenz Efavirenz Tenofovir Tenofovir Didanosine Didanosine

34. Patient 1 22 y/o man with AIDS CD4 122 VL > 750k DMAC 22 y/o man with AIDS CD4 122 VL > 750k DMAC 122 lbs 122 lbs Cr 1.4 Cr 1.4 Resistance testing: M184V, 215, 219, 82, 84 Resistance testing: M184V, 215, 219, 82, 84 Proposed regimen Proposed regimen Lopinavir/ritonavir Lopinavir/ritonavir Efavirenz Efavirenz Tenofovir: levels increased by renal failure and lopinavir/rtv Tenofovir: levels increased by renal failure and lopinavir/rtv Didanosine Didanosine

35. Patient 1 22 y/o man with AIDS CD4 122 VL > 750k DMAC 22 y/o man with AIDS CD4 122 VL > 750k DMAC 122 lbs 122 lbs Cr 1.6 Cr 1.6 Resistance testing: M184V, 215, 219, 82, 84 Resistance testing: M184V, 215, 219, 82, 84 Proposed regimen Proposed regimen Lopinavir/ritonavir Lopinavir/ritonavir Efavirenz Efavirenz Tenofovir Tenofovir Didanosine: levels increased by low weight, renal failure, and tenofovir Didanosine: levels increased by low weight, renal failure, and tenofovir

36. Patient 1 Considerations DrugDosage lopinavir/ritonavir tenofovir efavirenz didanosine

37. Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions DrugDosage lopinavir/ritonavir tenofovir efavirenz didanosine

38. Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions DrugDosage lopinavir/ritonavir 4 caps bid tenofovir efavirenz didanosine

39. Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions DrugDosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz didanosine

40. Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions DrugDosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz 600 mg daily didanosine

41. Patient 1 Considerations Low weight Renal failure [Ccr= 48 cc/min] Drug interactions DrugDosage lopinavir/ritonavir 4 caps bid tenofovir 300 mg every 48 hours* efavirenz 600 mg daily didanosine 100 – 125 mg daily?

42. Final Recommendations Look up all interactions using a computer or PDA Look up all interactions using a computer or PDA Avoid using drugs together which have not been studied Avoid using drugs together which have not been studied Pay close attention to body weight, hepatic and renal impairment Pay close attention to body weight, hepatic and renal impairment Follow liver enzymes and renal function closely Follow liver enzymes and renal function closely