Drug Interaction Study Between Lumefantrine and Lopinavir/Ritonavir
Condition: HIV Infections
MeSH terms: HIV Infections
Study type: Interventional
Phase: Phase 4

Summary: 
      With the roll out of antiretroviral therapy (ARV) for HIV across sub-Saharan Africa an
      unprecedented number of people will be commencing lifelong therapy. Current estimates are
      that 5-6 million people in sub-Saharan Africa require ART. At the same time, the World Health
      Organization (WHO) Roll Back Malaria campaign is aggressively promoting the use of
      artemether/lumefantrine as first-line therapy for malaria in this setting. Many patients in
      this setting have already become resistant to first-line ARV and have moved onto
      lopinavir/ritonavir (Kaletra) based second-line regimens. Kaletra is a potent inhibitor of
      Cytochrome P450 3A4 (CYP 3A4), an enzyme responsible for the metabolism of many drugs which
      is found predominantly in the liver and the gut. Lumefantrine, and to a lesser extent
      artemether, is extensively metabolized by CYP 3A4. Therefore when given to a patient already
      taking Kaletra for HIV, it is likely that elevated levels of these drugs in the patient will
      result. There is some concern that lumefantrine may be cardiotoxic due to its structural
      similarity to halofantrine which is known to cause irregular heart rhythms. This has not been
      borne out as yet in any studies performed with lumefantrine, however it is not known what
      levels will be achieved in patients when it is administered with a protease inhibitor such as
      Kaletra. The WHO has not addressed this issue in any of its previous policy documents but has
      identified ARV-antimalarial drug interaction studies as a research priority. This single dose
      pharmacokinetic (PK) study aims to compare the levels of lumefantrine/artemether that result
      when it is given to a patient on Kaletra with patients not on any ARV. Data generated by this
      study will help address this important knowledge gap which has been identified by WHO and
      others as meriting urgent investigation.
    

Detailed description: 
      In 2004 there were an estimated 40 million people living with HIV, 95% of whom live in the
      developing world. It is estimated that 5-6 million of these require antiretroviral therapy
      (ARV) now, and this number will continue to rise. At the recent G8 summit in Gleneagles,
      Scotland, a unanimous commitment to Universal Access to ARV by 2010 was made. This will
      result in an unprecedented number of individuals, predominantly in the developing world,
      commencing lifelong therapy with ARV. Currently the recommended second-line therapy for ARV
      is a combination of two nucleoside reverse-transcriptase inhibitors (NRTI) and a protease
      inhibitor (PI). The most widely recommended PI at this time in sub-Saharan Africa is Kaletra
      (Abbott Laboratories) which is a combination of lopinavir, a PI, and ritonavir, a PI that is
      a potent enzyme inhibitor and acts as a pharmacokinetic enhancer for lopinavir. Although
      Kaletra is highly effective in the treatment of HIV, it is a drug that has significant
      potential for drug-drug interactions. These are largely due to ritonavir's, and to a lesser
      extent lopinavir's, potent inhibition of Cytochrome P450 3A4 (CYP 3A4), which can result in
      dramatically raised levels of any co-administered drug metabolised by this same route.

      Unfortunately these same people are also the constant victims of the malaria pandemic. There
      are at least 300 million acute cases of malaria each year globally, resulting in more than a
      million deaths, 90% of which occur in Africa. Increasing resistance to anti-malarials such as
      chloroquine, amodiaquine, fansidar, sulphadoxine-pyrimethamine (SP) in East and West Africa
      has led the WHO to recommend artemether-lumefantrine (Coartem - Novartis) as first-line
      therapy for malaria for adults and children. By 2004, fourteen countries in sub-Saharan
      Africa had adopted this as official policy, with the WHO applying pressure on the rest to
      follow as part of its Roll Back Malaria Campaign. The WHO's recommendations however makes no
      specific reference to the use of artemether-lumefantrine in HIV positive patients,
      particularly in patients who are being treated with ARV, although in it's document "Malaria
      and HIV/AIDS Interactions and Implications: Conclusions of a Technical Consultation Convened
      by WHO, 23-25 June, 2004" it states that "additional research on interactions between
      antiretroviral and antimalarial drugs is urgently needed." Coartem is already being used in
      sub-Saharan Africa as treatment for malaria in HIV-positive individuals on ARV, and this
      trend is likely to continue given the lack of explicit guidelines on their concomitant
      administration.

      Lumefantrine and artemether are both extensively metabolized by CYP 3A4. To date, no data
      exist with regard to the potential interactions of these drugs with PI. This gives rise for
      concern, in particular in the case of lumefantrine, that patients administered both drugs
      concurrently are likely to have elevated lumefantrine levels with potential for associated
      toxicity. Lumefantrine, unlike its predecessor halofantrine, does not seem to prolong the QT
      interval (which can lead to adverse cardiac events), however there is no data with regard to
      the potential for adverse events when administered with PI. Given the unknown potential for
      interactions when co-administered with PI, in association with the massive roll out that is
      occurring of both these drugs across sub-Saharan Africa and their concomitant use in
      patients, it is essential that these issues be addressed to inform policy as a matter of
      urgency.

      Preliminary or supportive data:

      Artemether is metabolized via CYP 3A4 to dihydroartemisinin (although both compounds have
      antimalarial activity, dihydroartemisinin has greater potency). Inhibition of CYP 3A4 would
      reduce dihydroartemisinin but increase artemether and potentially increase the short
      half-life of artemether (1 - 2 hours). The effects of PI and NNRTI are unclear.

      Lumefantrine and halofantrine are extensively metabolized by CYP 3A4. Inhibition of
      halofantrine metabolism could potentially prolong QT interval; given the narrow therapeutic
      index of this drug, combination with PI is contraindicated and NVP and EFV should be used
      with caution. Lumefantrine does not seem to prolong the QT interval and is much safer than
      halofantrine. In a single-dose study in combination with ketoconazole, a potent inhibitor of
      CYP 3A4, lumefantrine Cmax and AUC were doubled but no clinically significant QT effects were
      noted. Nevertheless, the Novartis Drug Monograph for Coartem lists CYP 3A4 inhibitors,
      including Ketoconazole and PI, under precautions/contraindications, despite stating in the
      same document that "dose adjustment of coartemether appears to be unnecessary when
      administered in association with ketoconazole or another potent inhibitor of CYP 3A4
      activity." No studies however exist in the literature or are listed in the product monograph
      addressing the important potential interaction with PI. The WHO and a recent editorial in
      AIDS identify an urgent need for interaction data and state that studies should be
      prioritized to address this gap in knowledge. Currently in practice, coartem is being
      administered to patients in sub-Saharan Africa and WHO policy and guidelines do not address
      this issue.

      Significance of the study:

      As outlined in the background, this study is of urgent public health importance in the
      developing world where ARV and anti-malarials are used concomitantly. There are increasing
      numbers of HIV patients in Uganda moving on to second-line therapy with Kaletra and these are
      already being treated with coartem where they can afford it. The consequences of prescribing
      these drugs concomitantly have not been elucidated. The WHO has made no recommendations to
      guide treatment in this situation and there are no study data available to guide policy. Data
      generated by this study would help address this important gap which has been identified by
      WHO and others as meriting urgent investigation.

      Hypothesis:

      That administration of the lumefantrine and artemether-containing antimalarial combination
      therapy (Coartem) to HIV-positive patients receiving lopinavir/ritonavir (Kaletra) results in
      increased exposure to lumefantrine and/or artemether thus putting the patient at increased
      risk of toxicity from these drugs.
    

Intervention name(s): Lumefantrine - lopinavir/ritonavir drug interaction; Lumefantrine only arm
Intervention type(s): Drug; Drug
Intervention description(s): Lumefantrine 480 mg co-formulated with artemether 80 mg administered as single dose to HIV-positive adults receiving lopinavir/ritonavir 400 mg/100 mg twice daily; Lumefantrine 480 mg co-formulated with artemether 80 mg administered as a single dose to antiretroviral naive HIV-positive patients
Other intervention name(s): Coartem tablets; Kaletra/Aluvia tablets; Coartem tablets
Intervention MeSH terms: Ritonavir; Lopinavir; Lumefantrine; Artemether, Lumefantrine Drug Combination
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: HIV; lumefantrine; lopinavir; Africa; Antimalarials; treatment naïve