5th INTER COUNTRY MEETING OF NATIONAL MALARIA PROGRAMME MANAGERS

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5th INTER COUNTRY MEETING OF NATIONAL MALARIA
PROGRAMME MANAGERS
Drug policy updates for malariafree countries
and countries with residual foci
Presented by Dr A. Bosman Prompt Access to
Effective Treatment Malaria Strategy and Policy
Roll Back Malaria Department
Damascus, Syrian Arabic Republic, 21 - 23 June
2005
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P. falciparum resistance to sulfadoxine/pyrimetham
ine Source WHO global database on drug
resistance 1996-2004
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P.vivax malaria distribution and Reported
Treatment or Prophylaxis Failures or True
Resistance, 2004
Vivax resistance to CQ confirmed in Guyana,
Indonesia and Peru
Source WHO RBM Department, 2004
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Malaria treatment policy
for malariafree countries and countries
with residual foci

• Dynamics of local malaria transmission
• Species and sensitivity to antimalarial medicines
  
• Endemicity/receptivity/epidemic potential
• Pattern of imported and introduced malaria
• Malaria control measures
• Case detection (airport, borders, inland)
• Access to treatment, especially for foreigners
  (including illegal workers)
• Vector control guided by case reporting to
  eliminate residual foci and contain epidemic risk
  

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Which antimalarial drugs?

• WHO Informal Consultation on Use of
  Antimalarial Drugs (November 2000, Geneva)
• The potential value of drug combinations, notably
  those including an artemisinin derivative (ACT),
  to improve efficacy, delay development of
  drug-resistance and prolong the useful
  therapeutic life of antimalarial drugs was widely
  accepted.
• Recommended that combinations that do not contain
  an artemisinin derivative could be an interim
  option for reasons of cost and accessibility in
  some countries

NO LONGER RECOMMENDED
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Rationale for antimalarial combination therapy

• Combining two or more antimalarial drugs with
  different modes of action (and thus drug targets)
  provides two main advantages.
• First cure rates are usually increased.
• Second, in the rare event that a mutant parasite
  which is resistant to one of the drugs arises
  de-novo during the course of the infection, it
  will be killed by the other drug. This mutual
  protection prevents the emergence of resistance.
• For both these advantages it is necessary that
  both partner drugs in a combination are
  independently effective.
• Balanced against these two advantages are the
  increased costs and the increased risks of
  adverse effects (although in some cases such as
  the combination of artesunate mefloquine
  adverse effects such as vomiting are reduced).

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The choice of artemisinin combination therapy
(ACT)

• There are now more trials involving artemisinin
  and its derivatives than other antimalarial
  drugs, so although there are still gaps in our
  knowledge, there is a reasonable evidence base on
  safety and efficacy from which to base
  recommendations.

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CONTROLLED RANDOMISED, DOUBLE-BLIND TRIALS OF
ARTESUNATE COMBINED WITH PYRIMETHAMINE/SULFA,
CHLOROQUINE OR AMODIAQUINE
S/P600pts (Epicentre/MSF)
ADQ 360pts
CLQ 400pts?
S/P 600pts Completed
S/P 400pts
S/P600pts (Wellcome-Trust)
CLQ 300pts
CLQ 300pts
S/P 600pts
CLQ 400pts underway
ADQ 300pts underway
ADQ 400pts
S/P 450pts
TIMELINES start end PK studies in
volunteersJul-98 Jun-99 Clinical
studies Nov-98 Oct-99 PCR and population
PK May-99 Dec-99 Meta-analysis Nov-99 Mar-00
ONE / THREE studies completed
Evidence WHO/TDR multicenter trial
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Artemisinin-based combination therapies

• Rapid and sustained reduction of the parasite
  biomass
• Rapid resolution of clinical symptoms
• Reduction of gametocyte carriage
• Duration of treatment 2-3 days in combination
  (7 days in monotherapy)
• Broad stage specificity

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Plasma concentration ()
Mfq
Pyr
Qn
Cq
Piperaquine
Art
0
1
2
3
4
WEEKS
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Therapeutic response
Cure rate ()
Days of treatment
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Elimination of gametocytes
Uganda S/P /- AS
Kenya AQ /- AS
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Cure rates documented in different trials
Artemether- lumefantrine
Artemether/artesunate mefloquine
Dihydroartemisinin piperaquine
100
90
80
70
60
50
40
30
20
10
0
(Courtesy of Prof N.White)
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Recommended ACTArtesunatemefloquine

• High levels of resistance only found in
  SouthEast Asia (Cambodia, Thailand, Myanmar, and
  Vietnam) and artesunate-mefloquine combination is
  very likely to be effective everywhere.
• The artesunate dose used has been 4mg/kg/day for
  3 days. The mefloquine 25mg base/kg (higher dose)
  is more effective and is less likely to select
  for resistance.
• Day 42 failure rates of up to 50 with mefloquine
  monotherapy in the 8 comparative trials reported
  to date, have still been associated with cure
  rates over 90 with the artesunate combination.
• The principle problems with AM are nausea and
  vomiting in young children, and central nervous
  system adverse effects (dizziness, dysphoria,
  nightmares, and less commonly seizures,
  encephalopathy or psychosis). Gastrointestinal
  intolerance can be reduced by splitting the dose
  (15mg base/kg on day 0 or day 1 followed 12-24
  hours later by 10mg base/kg has been most
  studied). Future fixed dose regimens will have
  4mg/kg artesunate and 8mg/kg of mefloquine per
  day for 3 days, and this is also a suitable
  regimen for separate tablets.

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Recommended ACT Artemether-lumefantrine

• P.falciparum shows some cross-resistance between
  lumefantrine and mefloquine, but highly
  lumefantrine resistant parasites have not been
  documented.
• The advantage of this combination is that
  lumefantrine is not available as monotherapy and
  has, therefore, never being used by itself for
  the treatment of malaria. Provided that there is
  adequate absorption of lumefantrine, this
  combination would be expected to be effective
  everywhere.
• The four dose regimen is no longer recommended,
  because it does not contain enough lumefantrine,
  and did not provide sufficiently high cure rates.
  It has now been superseded by the six-dose
  regimen.
• The principle problem with artemether-lumefantrine
  is variable oral absorption of lumefantrine,
  which may give rise to treatment failure as a
  result of inadequate blood concentrations.
  Absorption of lumefantrine is increased by
  coadministration with fats (food, milk) and
  improves as the patient recovers from illness.
  The combination is remarkably well tolerated.

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COMPARISON OF DIFFERENT COMBINATIONS
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Other antimalarials quinine

• Quinine continues to have an important role. Even
  in areas with reduced susceptibility (parts of
  SouthEast Asia and South America), quinine is
  still effective in these areas.
• Quinine should be combined with either a
  tetracycline or, in children, clindamycin. These
  antimalarial antibiotics are also given for seven
  days. These combined regimens achieve cure rates
  of over 90 even in areas of high level drug
  resistance.
• It is still the drug of choice for uncomplicated
  falciparum malaria in the first trimester of
  pregnancy.
• Quinine may also be part of second line treatment
  regimens, but it is not a standard first-line
  treatment because it must be given three times
  daily, and is poorly tolerated (bitter taste,
  nausea, tinnitus, dysphoria, giddiness a
  symptom complex named cinchonism). This reduces
  adherence to the seven day regimens which are
  needed to achieve high cure rates.

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Quinine (cont'd)

• Quinine has been combined with SP in shorter
  course regimens (usually 3 days of quinine
  followed by a full therapeutic dose of SP on day
  3) but these rely heavily on the efficacy of SP,
  and, given the better safety profile of the
  artemisinin derivatives, are no longer
  recommended.
• Oral quinine is also often given to complete a
  full seven days treatment following parenteral
  treatment for severe malaria. Serious adverse
  effects from oral quinine are unusual in
  uncomplicated malaria, although hypoglycaemia may
  occur in pregnant women in late pregnancy.

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Other antimalarials chloroquine

• Chloroquine is still treatment of choice for
  P.vivax, P.ovale, P.malariae, and the occasional
  monkey malaria which gets transmitted to humans,
  but for P.falciparum chloroquine can be relied
  upon only in Haiti and Central America, north of
  the Panama canal.
• In many other countries chloroquine is still the
  national policy recommended first-line
  antimalarial in the absence of recent trials.
  If in the surrounding or adjacent countries,
  there is high level chloroquine resistance, it
  is very unlikely that chloroquine is still
  sufficiently effective to be recommended. If
  there is genuine cause to believe chloroquine is
  effective in an area, and chloroquine is the
  currently recommended treatment, then in-vivo
  testing with a minimum of 28-day follow-up should
  be conducted.
• The combination of artesunate with chloroquine is
  not recommended. In countries where there is
  convincing recent evidence that chloroquine is
  still effective, then it is reasonable to
  continue this policy pending the arrival of
  inexpensive effective combinations.

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Chlorproguanil-dapsone

• This antifol-biguanide combination is given in a
  three day once daily regimen. It is more
  effective than SP against antifol resistant
  Plasmodium falciparum, but it is not effective
  against parasites with the IL-164 mutation in
  Pfdhfr (the gene encoding the antifol target
  dihydrofolate reductase). Parasites carrying this
  IL-164 mutation are prevalent in Asia and South
  America, but have not been confirmed in Africa
  where this drug has been evaluated. Nearly all
  recent clinical trials have been conducted with
  14 day follow-up so true efficacy is uncertain.
• Chlorproguanil-dapsone has been well tolerated in
  clinical trials, although there are some concerns
  over an increased risk of anaemia, which may
  result from dapsone induced haemolysis,
  especially in G6PD. An artesunate combination is
  under development but has not been evaluated yet.
  There is insufficient evidence at present to
  recommend this drug.

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Atovaquone-proguanil

• This combination of a naphthaquinone and
  biguanide is very effective against all malarias,
  including multi-drug resistant falciparum
  malaria. Atovaquone-proguanil is given in a three
  day once daily regimen. When atovaquone was
  evaluated alone initially, approximately 30 of
  patients with falciparum malaria had recrudescent
  infections resulting from the selection of highly
  atovaquone-resistant parasites. This is
  considerably reduced by the addition of
  proguanil.
• Because the two drugs have linked mechanisms of
  action, they are not considered as a combination
  treatment. A triple combination of
  artesunate-atovaquone-proguanil was highly
  effective against multi-drug resistant malaria in
  one large trial conducted in NW Thailand.
• Atovaquone-proguanil is very well tolerated with
  no serious adverse effects. The main problem is
  the high cost of manufacturing atovaquone. Thus
  while this continues to be a useful drug for the
  treatment of travelers, and in prophylaxis, it is
  too expensive for large scale deployment in
  endemic areas.

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51 countries have adopted ACTs
25 are deploying ACTs
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New ACTs in the pipeline
ASMQ blister
AS/Lapdap FDC AS/PRN FDC
ASS/P blister ASAQ blister
ART/LUM
DHA/PPQ FDC
AS/MQ FDC AS/AQ FDC
Péroxide synthétiques en combinaisons?
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Interesting New Developments

• This new anti-malarial drug dihydroartimisinin
  (40mg) piperaquine (320mg) (Artekin ), has
  been registered in PRC (China)
• Early clinical trials showed eradication rates of
  the malarial parasite in gt97 of patients tested
  (d56).
• Short, two-day treatment schedule

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