Drug-drug interaction Satellite Workshop
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Transcript of Drug-drug interaction Satellite Workshop
Drug-drug interaction Satellite Workshop
HIV Malaria Co-infection
M Lamorde MRCP, PhD
• Malaria: major cause of morbidity and mortality in tropics
• Treatment: artemisinin derivatives are critical for eradication of plasmodium falciparum (responsible for greatest burden)
• Epidemiology: significant geographic overlap with HIV • Complex interactions: pathogenesis, therapeutics
• Focus: malaria HIV drug interactions in resource-limited settings
Malaria and HIV
Uganda: recommended drugs
Malaria treatment• Uncomplicated malaria
– artemether/lumefantrine– artesunate/amodiaquineAlternative: DHA/piperaquine (previously oral quinine)
• Severe malaria– parenteral quinine– parenteral artesunate
Uganda: recommended drugs
Antiretroviral therapy• First-line (NNRTI-based)
– efavirenz – nevirapine
• Second-line (PI-based)– lopinavir/ritonavir– atazanavir/ritonavir
Uganda: recommended drugs
Antiretroviral therapy• First-line (NNRTI-based)
– efavirenz – nevirapine
• Second-line (PI-based)– lopinavir/ritonavir– atazanavir/ritonavir
CYP3A4 inducers
Uganda: recommended drugs
Antiretroviral therapy• First-line (NNRTI-based)
– efavirenz – nevirapine
• Second-line (PI-based)– lopinavir/ritonavir– atazanavir/ritonavir
CYP3A4 inhibitors
Potential for interactions with ARVs
Antimalarial drug Metabolic pathwayQuinine CYP3A4, 2C19
Artesunate/amodiaquine CYP3A4, 2A6
Artemether/lumefantrine CYP2C19, 3A4
Chloroquine CYP2C8, 2D6, 3A4
Atovaquone/proguanil Glucuronidation, 2C19
Potential for interactions with ARVs
Antimalarial drug Metabolic pathwayQuinine CYP3A4, 2C19
Artesunate/amodiaquine CYP3A4, 2A6
Artemether/lumefantrine CYP2C19, 3A4
Chloroquine CYP2C8, 2D6, 3A4
Atovaquone/proguanil Glucuronidation, 2C19
Potential interactions
Malaria treatment• Uncomplicated malaria
– artemether/lumefantrine– artesunate/amodiaquineAlternative: DHA/piperaquine(previously oral quinine)
• Severe malaria– parenteral quinine– parenteral artesunate
Antiretroviral therapy• First-line (NNRTI-based)
– efavirenz – nevirapine
• Second-line (PI-based)– lopinavir/ritonavir– atazanavir/ritonavir
Case
• NGN, F, 43 yrs, HIV diagnosis (2005)
• Management– CTX 960 mg OD (since 2005)– AZT/3TC/EFV (since 2008)
baseline CD4 108 cells/µL– CD4 (2011) 765 cells/µL
May 2012• Loss of appetite, fever,
occasional vomiting X 1 week• Self medication with
antimalarials (likely artemether/lumefantrine)
• No improvement
Infectious Diseases Institute, Kampala
Case
• NGN, F, 43 yrs, HIV diagnosis (2005)
• Management– CTX 960 mg OD (since 2005)– AZT/3TC/EFV (since 2008)
baseline CD4 108 cells/µL– CD4 (2011) 765 cells/µL
May 2012• Loss of appetite, fever,
occasional vomiting X 1 week• Self medication with
antimalarials (likely artemether/lumefantrine)
• No improvement
plasmodium falciparum
Options: AZT/3TC/EFV plus
quinine
?
Options: AZT/3TC/EFV plus
quinine
EVIDENCE:No data for efavirenz, some data for nevirapine• PK: In healthy volunteers receiving nevirapine,
33% lower quinine AUC and 36% lower Cmax
– Soyinka et al. J Pharm Pharmacol (2009)
• Efficacy: 1 case report of worsening malaria during quinine therapy – Uriel A. Int J STD AIDS (2011)
Options: AZT/3TC/EFV plus
artesunate/amodiaquine
?
Options: AZT/3TC/EFV plus
artesunate/amodiaquine
EVIDENCE:• Safety: First two healthy volunteers in a trial
developed significant transaminase elevations with amodiaquine exposure increased 115% & 302%. No artemisinin data.– German P et al. J CID (2007)
• Safety: Higher risk of neutropenia among HIV-infected children on antiretroviral therapy– Gasasira AF et al. CID (2008)
Options: AZT/3TC/EFV plus
artemether/lumefantrine
?This is what we did
Options: AZT/3TC/EFV plus
artemether/lumefantrine
EVIDENCE:• PK: In 30 Ugandan HIV positive patients without
malaria, artemether, DHA, lumefantrine concentrations were reduced by 77%, 75% and 55%, respectively.– Byakika-Kibwika P IAC 2012 TUPE-054
• PK: Similar reductions seen with rifampicin – Lamorde et al 51st ICAAC 2011
Symptoms resolved with artemether/lumefantrine treatment and patient continues ongoing HIV care at IDI
Outcome
– Self-medication with antimalarials and limited capacity for pharmacovigilance in resource-limited settings
– Efavirenz and nevirapine lower exposure of critical malaria drugs
– Clinical outcomes data needed
– ? Potential for resistance
Issues for discussion
How about malaria treatment for patients receiving protease inhibitors?
Case
• AK, M, 52 yrs, city businessman• HIV diagnosis (2004)
• Management– CTX 960 mg OD (since 2004)– d4T/3TC/NVP (since 2004)
baseline CD4 77 cells/µL– VL 17,000 copies (2008)– TDF/3TC/LPV/r (since 2008)– Last CD4 (2011) 350 cells/µL June 2012
• Low grade fever (on and off)• Blood film: malaria
• Referred to heart institute 2011• ECG normal• Blood pressure normal• Cholesterol
– Total: 230 mg/dL– HDL: 50 mg/dL
Options: Lopinavir/ritonavir plus
quinine
?
Options: Lopinavir/ritonavir plus
quinine
EVIDENCE:
• PK: In healthy volunteers, ritonavir increased the AUC and Cmax of quinine four-fold. – Soyinka et al. Br J Clin Pharmacol (2010)
• Safety: ? Potential for increased toxicity at standard doses
Options: Lopinavir/ritonavir plus
artemether/lumefantrine
?
Options: Lopinavir/ritonavir plus
artemether/lumefantrine
EVIDENCE:• PK: Ugandan HIV+ patients without malaria (n = 32), lumefantrine
concentrations increased by 386% while artemether decreased by 43%– Byakika-Kibwika P, J Antimicrob Chemother (2012)
• PK: Lumefantrine markedly higher in SA patients on LPV/r– T Kredo,CROI 2012 (Paper # 613)
• Efficacy: Randomized trial in Ugandan HIV+ children (n=176): 43% lower risk of malaria recurrence in lopinavir/ritonavir arm versus NNRTI arm.– Achan J, CROI 2012 (Paper #26)
Safety?
Options: Lopinavir/ritonavir plus
EVIDENCE:• Safety: Structurally similar to halofantrine which causes QT prolongation
Single dose studies: No QTc prolongation in healthy volunteers or Ugandan patients• German P, JAIDS 2009; Byakika-Kibwika P, Chem Res and Pract, 2011
• However, lumefantrine accumulates with repeated dosing and no safety data with six-dose regimen
artemether/lumefantrine
www.hiv-druginteractionslite.org
• Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala
• Ivan Mambule• Jane Achan• Pauline Byakika-Kibwika
Acknowledgements