Drug-drug interaction Satellite Workshop HIV Malaria Co-infection M Lamorde MRCP, PhD

Malaria and HIV 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

Uganda: recommended drugs Malaria treatment Uncomplicated malaria artemether/lumefantrine artesunate/amodiaquine Alternative: 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 pathway Quinine CYP3A4, 2C19 Artesunate/amodiaquine CYP3A4, 2A6 Artemether/lumefantrine CYP2C19, 3A4 Chloroquine CYP2C8, 2D6, 3A4 Atovaquone/proguanil Glucuronidation, 2C19 ATOVAQUONE/PROGUANIL NOT MENTIONED IN UGANDA GUIDELINES SO WILL YOU COMMENT?

Potential for interactions with ARVs Antimalarial drug Metabolic pathway Quinine CYP3A4, 2C19 Artesunate/amodiaquine CYP3A4, 2A6 Artemether/lumefantrine CYP2C19, 3A4 Chloroquine CYP2C8, 2D6, 3A4 Atovaquone/proguanil Glucuronidation, 2C19 ATOVAQUONE/PROGUANIL NOT MENTIONED IN UGANDA GUIDELINES SO WILL YOU COMMENT?

Potential interactions Malaria treatment Uncomplicated malaria artemether/lumefantrine artesunate/amodiaquine Alternative: 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 May 2012 Loss of appetite, fever, occasional vomiting X 1 week 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 NICE CASE. MAYBE STOP AFTER THE NO IMPROVEMENT TO GET PANEL COMMENTS BEFORE PROCEEDING TO THE DIAGNOSIS? Infectious Diseases Institute, Kampala

plasmodium falciparum 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 NICE CASE. MAYBE STOP AFTER THE NO IMPROVEMENT TO GET PANEL COMMENTS BEFORE PROCEEDING TO THE DIAGNOSIS? plasmodium falciparum

Options: AZT/3TC/EFV plus quinine ? Will you be asking the Panel if they would treat this patient with 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) Will you be asking the Panel if they would treat this patient with Quinine?

Options: AZT/3TC/EFV plus artesunate/ amodiaquine ? Question to Panel – is this a realistic option?

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) Question to Panel – is this a realistic option?

Options: AZT/3TC/EFV plus artemether/ lumefantrine This is what we did ? So the issues now are: the patient has already self-medicated with ART/LUM; the magnitude of the interaction To Panel – would you proceed?

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 So the issues now are: the patient has already self-medicated with ART/LUM; the magnitude of the interaction To Panel – would you proceed?

Outcome Symptoms resolved with artemether/lumefantrine treatment and patient continues ongoing HIV care at IDI

Issues for discussion 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

How about malaria treatment for patients receiving protease inhibitors? Any chance that this could be made into a second case, even if it is brief. I think you could develop the cardiotoxicity issue a bit – this will certainly be of interest.

Case June 2012 Low grade fever (on and off) Blood film: malaria 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 Referred to heart institute 2011 ECG normal Blood pressure normal Cholesterol Total: 230 mg/dL HDL: 50 mg/dL June 2012 Low grade fever (on and off) Blood film: malaria

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 artemether/ lumefantrine 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

Acknowledgements www.hiv-druginteractionslite.org Infectious Diseases Institute, Makerere University College of Health Sciences, Kampala Ivan Mambule Jane Achan Pauline Byakika-Kibwika Acknowledgements