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


Antiretroviral therapy• First-line (NNRTI-based)

– efavirenz – nevirapine

• Second-line (PI-based)– lopinavir/ritonavir– atazanavir/ritonavir





CYP3A4 inducers





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




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

?


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)


artesunate/amodiaquine

?


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)


artemether/lumefantrine

?This is what we did



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

?


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



?



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?


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


www.hiv-druginteractionslite.org

• Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala

• Ivan Mambule• Jane Achan• Pauline Byakika-Kibwika

Acknowledgements

Documents

Drug-drug interaction Satellite Workshop