Docstoc

Monitoring

Document Sample
Monitoring Powered By Docstoc
					         Monitoring antimalarial
           drug efficacy and
               resistance




                                  Dr P. Ringwald
                             Global Malaria Programme

1|   RAVREDA, Washington DC, USA 10 April 2011
WHO standardized protocol for the
assessment of therapeutic efficacy
 Gold standard to monitor drug efficacy
  and update drug policy
 Adopted by all the MoH and most of
  research institutes
 Designed for all drugs, including ACTs
 Follow-up according to the half-life of the
  drug (28 days follow-up as standard)
 Based on radical cure (all transmission
  area)



  2|   RAVREDA, Washington DC, USA 10 April 2011
                   Threshold levels for changing
                     malaria treatment policy


% clinical failures (14 d f/up)                     % failures (14 d f/up)   % failures (28 d f/up)

                                   Change            Parasitological
                                                        failures
 25%                                                                   25%
                                                             +
                          Action                          Clinical
                                                          failures                   Parasitological
15%                                                                    15%              failures
                  Alert                                                       10%
 5%                                                                    5%
          Grace
    0                                                                  0         0

            WHO criteria 1998                        WHO criteria 2003        WHO criteria 2005

   3|   RAVREDA, Washington DC, USA 10 April 2011
                   WHO/GMP Guidelines




     2004                        2006
                                                  2007
                                                         2008



4|    RAVREDA, Washington DC, USA 10 April 2011
                                  Challenges

 Routine monitoring of ACTs
     – Most of the countries carried out TET to update drug policy
     – Rarely as a routine activity (change of sites, personnel, decentralization)
 Funding
     – GF, PMI (USAID), WB and bilaterals
     – Gaps for some countries and absence of sustainability
 "Less but better studies"
     – More expensive
          •   Longer follow-up
          •   More QA and QC
          •   PCR becomes compulsory
          •   Set up national or regional reference centres for molecular biology


5|   RAVREDA, Washington DC, USA 10 April 2011
                                   Objectives
 General objective
     – to assess the therapeutic efficacy and safety of first and second line drugs for the
       treatment of uncomplicated P. falciparum malaria
 Specific objectives
     – to measure the clinical and parasitological efficacy by determining the proportion
       of patients with Early Treatment Failure (ETF), Late Clinical Failure (LTF), Late
       Parasitological Failure (LPF), or with an Adequate Clinical and Parasitological
       Response (ACPR) as indicators of efficacy;
     – to differentiate recrudescences from new infections by the Polymerase Chain
       Reaction (PCR) analysis (mandatory in all areas);
     – to evaluate the incidence of adverse events;
     – to formulate recommendations and to enable the Ministry of Health to make
       informed decisions about the possible need for updating of the current national
       antimalarial treatment guidelines.



6|   RAVREDA, Washington DC, USA 10 April 2011
                          Study design (1)
 Sampling strategy
     – One arm study
     – Comparative study
          • Non-inferiority trial if comparison of 2 highly effective medicines
          • Superiority if comparison of highly effective vs failing medicine
 Study sites
     –   Sentinel site network
     –   Limited number of sites (4-8)
     –   Represent all epidemiological settings, easy to access and to supervise
     –   Additional sites if epidemics or high failure rate reported or early warning system
         (in vitro-MM)
 Study population
     – patients all age group diagnosed with uncomplicated P. falciparum malaria and
       having given (if adults are included) or whose parents or guardians have given an
       informed consent for study inclusion and assent in children as appropriate.

7|   RAVREDA, Washington DC, USA 10 April 2011
                          Study design (2)

 Antimalarial drugs
     – First and second line drugs according the national guidelines
     – Regimens according to WHO treatment guidelines
     – New antimalarial combination if need to change policy
 Timing and duration of study
     – During the malaria transmission season
     – Follow-up of 28 days minimum
 Data corrected with genotyping
     – To distinghuish between recrudescence and reinfection
 Additional tools (but not mandatory)
     – In vitro, molecular markers for drug resistance, pharmacokinetic dosages


8|   RAVREDA, Washington DC, USA 10 April 2011
                               Classification
 ETF
      – development of danger signs or severe malaria on D1, D2, D3 in
        presence of parasitemia
      – parasitemia on D2 higher than D0
      – parasitemia on D3 > 25% count D0
      – parasitemia on D3 with axillary temperature > 37.5°C
 LCF
      – development of danger signs or severe malaria after Day 3 in the
        presence of parasitaemia without previously meeting any of the
        criteria of early treatment failure;
      – Presence of parasitaemia and axillary temperature > 37.5°C on any
        day from Day 4 to Day 28, without previously meeting any of the
        criteria of early treatment failure
 LPF
      – Presence of parasitaemia on any day from Day 7 to Day 28, and
        axillary temperature < 37.5°C, without previously meeting any of the
        criteria of early treatment failure or late clinical failure
 ACPR
      – Absence of parasitemia on Day 28 irrespective of axillary temperature
        without previously meeting any of the criteria of early treatment
        failure or late clinical or parasitological failure
9|   RAVREDA, Washington DC, USA 10 April 2011
                                        Analysis

 Kaplan Meier analysis
       – calculation up the last day of follow-up
 Per protocol analysis
       – assume that withdrawn and excluded patients are not a
         biased group
       – Ni = number of patients included, Na = number of patients
         analysed
       – Na = Ni -WTH-LFU
       – prevalence
          – WTH+LFU/Ni
          – ETF/Na; LCF/Na; LPF/Na; ACPR/Na


10 |   RAVREDA, Washington DC, USA 10 April 2011
                         Quality assurance
         • Drugs
               – batch
               – field test kit
               – reference laboratory
         • Microscopy
               – staining
               – parasite count
         • Temperature, body weight
         • Data management
               – CRF
               – data entry
               – data analysis


11 |   RAVREDA, Washington DC, USA 10 April 2011
       Genotyping to distinguish between
         reinfection and recrudescence
   Compulsory for TET (longer follow-up)
   Sampling D0, D7, D14, D21, D failure, D28
   Genotyping only D0 and D failure
   Consensus on standardization during co-
    sponsored WHO MMV meeting
     – Sampling scheme
     – Methods of blood sampling and sample
       storage
     – Genotyping strategy
     – Analyses and outcome classification
     – Quality control
     – Genotyping of P. vivax




    12 |   RAVREDA, Washington DC, USA 10 April 2011
                                 Other issues
 Ethical clearance
       – National (ethical committee or MoH) and WHO
 Funding mechanism
       – Depends on Regions/HQ
 Registration
       – A clinical trial for the purpose of registration is defined as any research study that
         prospectively assigns human participants or groups of humans to one or more
         health-related interventions to evaluate the effects on health outcomes.
         Interventions include but are not restricted to drugs, cells and other biological
         products, surgical procedures, radiological procedures, devices, behavioral
         treatments, process-of-care changes, preventive care, etc. It is possible to have
         randomized studies of diagnostic tests (or even of the impact of a survey) and
         these would need to be registered as they would evaluate the impact of the test
         on one or more health outcomes.
       – Current Controlled Trials (CCT) using the link http://www.controlled-
         trials.com/isrctn/submission/.
13 |   RAVREDA, Washington DC, USA 10 April 2011
                                             Vivax

 Major differences with falciparum protocol:
       – Inclusion criteria
            • Parasitemia > 250 ml
            • History of fever 48 hours
       – Classification
            • Same as falciparum or simplified
       – Chloroquine blood concentration
            • D7, D failure, D 28, D0
            • 100 ml on filter paper
       – Genotyping not useful for public health


14 |   RAVREDA, Washington DC, USA 10 April 2011
               Other tools to monitor drug resistance

 Pros                         In vitro tests
       –    Multiple tests possible
       –    Only tools to monitor single drugs
       –    Early warning system
       –    WHO field manual
 Cons
       – Correlation with clinical outcome not
         fully demonstrated
       – Lack of standardization
       – Resistance threshold not validated
       – Numerous methodologies
       – Not used to guide drug policy change
       – Training needed




15 |       RAVREDA, Washington DC, USA 10 April 2011
       Other tools to monitor drug resistance

 Pros                           PCR/RFLP analysis of chloroquine resistance marker pftcrt T76

       –    Multiple tests possible
       –    Sampling easy to obtain
       –    Early warning system
       –    WHO field manual

 Cons
       – Correlation with clinical outcome not
         fully demonstrated
       – Lack of standardization
       – Markers not available for all
         antimalarial drugs or combinations
       – Not used to guide drug policy change
       – Training needed

16 |       RAVREDA, Washington DC, USA 10 April 2011
       Monitoring therapeutic efficacy for countries
                   targeting elimination

 Detection of patients – active or passive?
 Routine in vivo monitoring of therapeutic efficacy with
  modified inclusion criteria (age, parasitemia, fever)
 Hospitalise all P. falciparum patients
       –   Tunisia and Morocco experience (≠ United Arab Emirates)
       –   Monitor all patients regardless of parasitaemia
       –   28 day follow up
       –   No loss to follow-up
       –   Use PCR for distinguishing between recrudescence and re-infection
 Use in vitro and molecular markers as additional tools

17 |    RAVREDA, Washington DC, USA 10 April 2011
                          Monitoring antimalarial drug resistance in the Americas. Proposal for regional plan of activities 2009 - 2010


                                                                   WHO TET              Systematic follow
                                          Epidemiol                                       up of 100% of
                                                                                                                                    Molecular      In vitro
                Drugs/ scheme              ogical                                        cases (very low     Drug       D3
                                                        One site       Multicenter                                                  markers        (ELISA)
                                            area                                           transmision
                                                                                             settings)

                                                                                                                    Brasil, Peru,
                                                                                                             ASU                                    Brasil
                                                          Brasil       Bra-Per-Bol       Bolivia (specific           Venzuela
                              ASU+MQ        Amazon
                                                                          Ven?               settings)
                                                                                                             MQ                     Peru, Brasil    Brasil

                                                                                                                      Brasil,
                                                                                                                                                    Brasil
                                                                            Bra                              ATM     Suriname,
                                                          Brasil                                                                                    (DHA)
                              Coartem       Amazon                       -Per-Bol           Suriname                  Guyana
                                                                           Ven?
                                                                                                             LUM

          P. falciparum
                                                                                                             ATM     Colombia                      Colombia
             First line                                                                                                                             (DHA)
                              Coartem       Pacific    no possible           Col            NA today
             schemes
                                                                                                             LUM

                                                                                                                     Ecuador,
                                                                                                             ASU
                                                                                        Ecuador (specific              Peru
                              ASU+SP        Pacific    no possible       Per-Ecu
                                                                                           settings)                                  Peru,
                                                                                                             SP
                                                                                                                                     Ecuador
                                                                                                                                    Honduras,
                                                                                                                                    Guatemala,
                                            Central    Check with       Hon -Gua          Mex, Bel, Nic,                            Nicaragua,
                              CQ(+PQ)                                                                        CQ          ?
                                            america   the countries     Pan - Cor          ELS, Cor                                  Panama,
                                                                                                                                    Haiti, Rep.
                                                                                                                                    Dominicana

                                            Amazon      Bra, Ven           Peru             NA today                     ?
            P. vivax
            First line           CQ                                                                          CQ
                                            Pacific                   Col, Per?, Ecu?       NA today                     ?
           treatment
                                            Central                   Hon, Gua, Pan,
                                                                                            NA today                     ?
                                            america                        Nic
                                                                           Sur
                              Coartem       Amazon       Brasil ?                           NA today
                                                                           Guy
            Alternative
        P vivax treatment

18 |
                              ASU+MQ        Amazon                                          NA today
       RAVREDA, Washington DC, USA 10 April 2011

				
DOCUMENT INFO