Drug-drug interaction Satellite Workshop

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

2. 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

3. Malaria treatment Uncomplicated malaria artemether/lumefantrine artesunate/amodiaquine Alternative: DHA/piperaquine (previously oral quinine) Severe malaria parenteral quinine parenteralartesunate Uganda: recommended drugs

4. Antiretroviral therapy First-line (NNRTI-based) efavirenz nevirapine Second-line (PI-based) lopinavir/ritonavir atazanavir/ritonavir Uganda: recommended drugs

5. Antiretroviral therapy First-line (NNRTI-based) efavirenz nevirapine Second-line (PI-based) lopinavir/ritonavir atazanavir/ritonavir Uganda: recommended drugs CYP3A4 inducers

6. Antiretroviral therapy First-line (NNRTI-based) efavirenz nevirapine Second-line (PI-based) lopinavir/ritonavir atazanavir/ritonavir Uganda: recommended drugs CYP3A4 inhibitors

7. Potential for interactions with ARVs

8. Potential for interactions with ARVs

9. Malaria treatment Uncomplicated malaria artemether/lumefantrine artesunate/amodiaquine Alternative: DHA/piperaquine (previously oral quinine) Severe malaria parenteral quinine parenteralartesunate Antiretroviral therapy First-line (NNRTI-based) efavirenz nevirapine Second-line (PI-based) lopinavir/ritonavir atazanavir/ritonavir Potential interactions

10. Case • NGN, F, 43 yrs, HIV diagnosis (2005) • Management • CTX 960 mg OD (since 2005) • AZT/3TC/EFV (since 2008) baseline CD4108 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

11. Case • NGN, F, 43 yrs, HIV diagnosis (2005) • Management • CTX 960 mg OD (since 2005) • AZT/3TC/EFV (since 2008) baseline CD4108 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

12. Options: AZT/3TC/EFV plus ?

13. Options: AZT/3TC/EFV plus • 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 PharmPharmacol (2009) • Efficacy: 1 case report of worsening malaria during quinine therapy • Uriel A. Int J STD AIDS (2011)

14. Options: AZT/3TC/EFV plus ?

15. Options: AZT/3TC/EFV plus • 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)

16. Options: AZT/3TC/EFV plus This is what we did ?

17. Options: AZT/3TC/EFV plus • 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

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

19. 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

20. How about malaria treatment for patients receiving protease inhibitors?

21. Case • AK, M, 52 yrs, city businessman • HIV diagnosis (2004) • Management • CTX 960 mg OD (since 2004) • d4T/3TC/NVP (since 2004) baseline CD477 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

22. Options: Lopinavir/ritonavir plus ?

23. Options: Lopinavir/ritonavir plus • EVIDENCE: • PK: In healthy volunteers, ritonavir increased the AUC and Cmax of quinine four-fold. • Soyinka et al. Br J ClinPharmacol (2010) • Safety: ? Potential for increased toxicity at standard doses

24. Options: Lopinavir/ritonavir plus ?

25. Options: Lopinavir/ritonavir plus • EVIDENCE: • PK: Ugandan HIV+ patients without malaria (n = 32), lumefantrineconcentrations increased by 386% while artemether decreased by 43% • Byakika-Kibwika P, J AntimicrobChemother (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)

26. Safety?

27. 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

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