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Antiretroviral Drug to Treat HIV Infection. Credit NIAID

Artemether-Lumefantrine / ARV PK Study Group

A meta-analysis of individual patient data (IPD) to determine the effect of antiretroviral (ARV) drug-drug interactions and HIV disease on artemether and lumefantrine pharmacokinetics (PK). The analysis aims to contribute evidence needed to inform recommendations on the use and optimal dosing of artemether-lumefantrine (AL) in HIV-infected patients.

Timeline

Data submissions have now closed, and analysis has been completed for the lumefantrine-ARV component. A draft publication is currently in circulation to study group members and submission is expected in Q4 2018.

This will be followed by the analysis relating to artemether, due for completion in Q1 2019.

Rationale

Despite AL being the most widely recommended treatment for uncomplicated malaria, and the large geographic overlap in malaria and HIV transmission areas, the effect of ARV drug-drug interactions and HIV-related disease on artemether and lumefantrine (and their metabolites, dihydroartemisinin, DHA, and desbutyl-lumefantrine respectively) PK is not yet clearly defined. Higher lumefantrine and artemether concentrations have been reported when AL is co-administered with protease inhibitors (1-5), and lower lumefantrine & artmether concentrations seen when AL is co-administered with efavirenz (1,6-9). The effects of nevirapine-based regimens on lumefantrine exposure have not been consistent, with some studies reporting unchanged or decreased lumefantrine concentrations (1,6,7,9) and others reporting increased lumefantrine concentrations (10,11) whereas the artemether and DHA exposure is significantly lowered with co-administration of nevirapine.  IPD meta-analyses are needed to resolve important questions, such as whether dosage adjustments should be considered when AL is co-administered with either efavirenz or protease inhibitors and understand any effects of nevirapine-based ARVs on lumefantrine exposure, and to determine whether HIV disease itself alters lumefantrine drug concentrations. 

Objectives

  • Define the effect of co-administration of ARVs on artemether, lumefantrine (and their metabolites’) exposure
  • Detect any HIV disease effect on artemether, lumefantrine (and their metabolites’) exposure
  • Determine whether ARV drug interactions and or HIV co-infection alter artemether-lumefantrine therapeutic efficacy

Inclusion criteria for data sets

  • Patients with or at risk of malaria OR healthy volunteers (both-HIV infected or uninfected)
  • Treated with AL (including full course and single dose in healthy volunteers)
  • HIV infected AND / OR treated with ARVs
  • Drug concentration(s) of artemether AND / OR lumefantrine (and metabolites) measured

Data standardisation and analysis

After upload to the WWARN Data Repository, data sets will be transformed, standardised and combined according to the WWARN Pharmacology and Clinical Data Management and Statistical Analysis Plans. The statistician appointed to the project will develop a statistical analysis plan specifically for the analysis, in collaboration with Study Group members.

 The combined databases will aim to include the following:

  • Demographics
  • Baseline patient characteristics
  • Clinical signs and symptoms over time
  • Date ARV started and current regimen
  • CD4 and viral load in HIV infected patients, if available
  • Dosing (mg/kg dose and dosing times) for antimalarials and ARVs
  • Lumefantrine (+ desbutyl-lumefantrine) concentration(s) and sample time(s)
  • Artemether (+ DHA) concentration(s) and sample time(s)
  • Parasite densities over time
  • Treatment outcome (including PCR, if available)
  • Haematology and biochemistry
  • Molecular markers of artemisinin and lumefantrine resistance

Study group governance and membership

The Study Group comprises participating investigators who contribute relevant data sets to the analysis. Data sets remain the property of the investigator. The Study Group will be asked to assist in the identification of any further relevant studies and will collectively make decisions with respect to data analysis plans and plans for publication, in line with the WWARN Publication Policy. The Study Group will be led by Dr Paolo Denti, Head of the Pharmacometrics Unit at the University of Cape Town and his post-doctoral student Dr Jose Francis (jose [dot] francis [at] uct [dot] ac [dot] za). For further information on WWARN Pharmacology, email Karen Barnes (karen [dot] barnes [at] wwarn [dot] org)" rel="nofollow">karen [dot] barnes [at] wwarn [dot] org)) or Elizabeth Allen (elizabeth [dot] allen [at] wwarn [dot] org(link%20sends%20e-mail)" rel="nofollow">elizabeth [dot] allen [at] wwarn [dot] org)

References

1. Hoglund RM, Byakika-Kibwika P, Lamorde M, Merry C, Ashton M, Hanpithakpong W, Day NP, White NJ, Äbelö A, Tarning J. Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications. Br J Clin Pharmacol. 2015 Apr;79(4):636-49.

2. Kakuda TN, DeMasi R, van Delft Y, Mohammed P. Pharmacokinetic interaction between etravirine or darunavir/ritonavir and artemether/lumefantrine in healthy volunteers: a two-panel, two-way, two-period, randomized trial. HIV Med. 2013 Aug;14(7):421-9.

3. Achan J, Kakuru A, Ikilezi G, Ruel T, Clark TD, Nsanzabana C, Charlebois E, Aweeka F, Dorsey G, Rosenthal PJ, Havlir D, Kamya MR. Antiretroviral agents and prevention of malaria in HIV-infected Ugandan children. N Engl J Med. 2012 Nov 29;367(22):2110-8.

4. Byakika-Kibwika P, Lamorde M, Okaba-Kayom V, Mayanja-Kizza H, Katabira E, Hanpithakpong W, Pakker N, Dorlo TP, Tarning J, Lindegardh N, de Vries PJ, Back D, Khoo S, Merry C. Lopinavir/ritonavir significantly influences pharmacokinetic exposure of artemether/lumefantrine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012 May;67(5):1217-23.

5. German P, Parikh S, Lawrence J, Dorsey G, Rosenthal PJ, Havlir D, Charlebois E, Hanpithakpong W, Lindegardh N, Aweeka FT. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr. 2009 Aug 1;51(4):424-9.

6. Maganda BA, Ngaimisi E, Kamuhabwa AA, Aklillu E, Minzi OM. The influence of nevirapine and efavirenz-based anti-retroviral therapy on the pharmacokinetics of lumefantrine and anti-malarial dose recommendation in HIV-malaria co-treatment. Malar J. 2015 Apr 25;14(1):179.

7. Maganda BA, Minzi OM, Kamuhabwa AA, Ngasala B, Sasi PG. Outcome of artemether-lumefantrine treatment for uncomplicated malaria in HIV-infected adult patients on anti-retroviral therapy. Malar J. 2014 May 30;13:205.

8. Huang L, Parikh S, Rosenthal PJ, Lizak P, Marzan F, Dorsey G, Havlir D, Aweeka FT. Concomitant efavirenz reduces pharmacokinetic exposure to the antimalarial drug artemether-lumefantrine in healthy volunteers. J Acquir Immune Defic Syndr. 2012 Nov 1;61(3):310-6.

9. Byakika-Kibwika P, Lamorde M, Mayito J, Nabukeera L, Namakula R, Mayanja-Kizza H, Katabira E, Ntale M, Pakker N, Ryan M, Hanpithakpong W, Tarning J, Lindegardh N, de Vries PJ, Khoo S, Back D, Merry C. Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother. 2012 Sep;67(9):2213-21.

10. Kredo T, Mauff K, Van der Walt JS, Wiesner L, Maartens G, Cohen K, Smith P, Barnes KI. Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients. Antimicrob Agents Chemother. 2011 Dec;55(12):5616-23.

11. Chijioke-Nwauche I, van Wyk A, Nwauche C, Beshir KB, Kaur H, Sutherland CJ. HIV-positive nigerian adults harbor significantly higher serum lumefantrine levels than HIV-negative individuals seven days after treatment for Plasmodium falciparum infection. Antimicrob Agents Chemother. 2013 Sep;57(9):4146-50