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Drugs and resistance: Artemisinin combination Therapies (ACT’s)

Source: TropIKA

Title of the session: Drugs and resistance: Artemisinin combination Therapies (ACT’s)

Date: 06 November 2009

Agenda item: Scientific session 39

Session theme: Antimalarial drugs and resistance: ACT’s

Meeting room: Tsavo ballroom II

Chair(s): Designated chairs were absent: Oluseye Bolaji –one of the presenters, chaired in lieu of the original chairs

Presenters:

• Billy Ngasala/Tanzania/Sweden
• HailleMariam Lemma/Ethiopia
• Julia Mwesigwa/Uganda
• Umberto D’Allesandro/Belgium
• David Sinclair/UK
• Simon Sensaline/Uganda
• Arthur Mpinbaza/Uganda
• Oluseye Bolaji/Nigeria

TropIKA rapporteur: George Obeng Adjei

Major topics:

• Effectiveness of artemether-lumefantrine in underfive children with uncomplicated malaria at community level in rural Tanzania: open label prospective study
• Community-level deployment of artemether lumefantrine with rapid diagnostic testing: effect on malaria mortality and health service utilization in a rural setting
• Pharmacokinetics of artemisinin combination therapies in Kampala, Uganda
• Pharmacokinetics of dihydroartemisinin and piperaquine in children with uncomplicated malaria in Burkina Faso
• Cochrane review of artemisinin-based combination therapy
• Implications of price and availability of ACT’s on malaria treatment in Uganda
• Comparing different artemisinin-based combination therapies in Uganda
• implication for policy
• Quality of artesunate-containing antimalarials marketed in Nigeria

Keywords:

• Artemisinin combination therapy
• pharmacokinetics
• drug resistance
• effectiveness
• meta-analysis

Scope:

• Effectiveness and community deployment of effective antimalarial therapies
• pharmacokinetics and influence of artemisinin combination therapies on drug resistance

REPORT ON ORIGINAL SESSION

Overview

The chair-in-proxy called the session to order saying he is sitting in for the designated chairperson(s). The session started with a presentation by Billy Ngasala, on the effectiveness of artemether-lumefantrine in children under the age of five within the context of the home-based malaria management strategy in a rural setting in Uganda, followed by a presentation on “effect of community-based deployment of artemether-lumefantrine on health service utilization and malaria morbidity and mortality in Ethiopia. The following two presentations were on pharmacokinetics of artemisinin-based combination therapies: Julia Mwesigwa presented data on the pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in Ugandan children, while Umberto D’Alessandro, who presented in stead of Halidou Tinto, spoke on the pharmacokinetics of dihydroartemisinin and piperaquine in children with uncomplicated malaria in Burkina Faso. David Sinclair then presented data on a meta-analysis of artemisinin-based combination therapies from within the framework of the Cochrane collaboration, while Arthur Mpinbaza presented data on the policy implications of a comparative analysis of different ACT regimens under different transmission settings in Uganda. This was then followed by a presentation by Oluseye Bolaji on the quality of artesunate-containing antimalarials marketed in Nigeria.

CONTEXT AND ISSUE

Malaria remains a major cause of morbidity and mortality in Africa; the WHO promotes the home-based malaria management strategy to increase access to ACT; artemisinin combination therapies have demonstrated excellent efficacy; however, there is little information on the effectiveness of ACT–after deployment at the community level, in rural and hard-to-reach areas of sub-Saharan Africa. There is also little information on the pharmacokinetics (PK) of commonly deployed ACT’s such as artemether-lumefantrine and artesunate-amodiaquine, and even fewer PK data on newer ACT’s such as dihydroartemisinin-piperaquine (DHA-P), for children in sub-Saharan Africa. Further, current WHO guidelines on guidelines requires that evidence for therapies and other interventions be based on i) systematic reviews and ii) grade assessment, and DHA-P has been demonstrated to be efficacious but there has been few-if any, of such systematic reviews to compare the relative advantages merits of ACT’s such as DHA-P. The WHO therefore, requested a review with the primary purpose of determining i) which of the available ACT’s is better and ii) where does DHA-P fit into the picture. There have also been previous studies –albeit with limitations – on ineffective and poor quality ACT’s from countries such as Nigeria, where a multitude of brands of ACT’s from different sources abound.

Key facts and figures

There is little information on the effectiveness of ACT’s after community deployment in rural and hard-to-reach settings, on the pharmacokinetics of ACT’s in children, and comparative assessment of various ACT regimens at the policy level. There are also reports of poor quality ACT’s on the market.

Initiatives on the ground; experience/s derived

Open label, non-comparative trial

Conventional pharmacokinetics study with non-compartmental analysis

Population pharmacokinetics study with Bayesian derivatives

Meta-analysis

Census survey

Systematic review of data from randomized clinical trials with the WHO 2009 outcome classification

High performance liquid chromatography and dissolution studies

Research Findings

• The PCR-adjusted cure rate for artemether-lumefantrine deployed under field conditions in Tanzania was 95.1% and 93% on days 28 and 42, respectively; however, there was more than 60% new/re-infection rate, and plasma lumefantrine concentrations were lower in patients with recrudescence.

• After community-based deployment of artemether-lumefantrine in rural Ethiopia, patient load at peripheral health facilities, total malaria case-load, number of cases of falciparum malaria, in-patient case-load, malaria parasite reservoir and the adjusted rate for malaria-specific mortality were lower in intervention districts compared to control districts.

• The half-lives of artemether and dihydroartemisinin in Ugandan children were comparable to reports from adults; however, the desethylamodiaquine exposure was higher in children compared to adults, while lumefantrine exposure was lower compared to reports from adults.

• The efficacy (PCR-adjusted) of DHA-P from a PK study in children in Burkina Faso was 96.7%, 89.6%, and 86.2% at days 28, 42 and 90, respectively; both drugs display variable absorption, and the key PK parameters were not different from adults.

• A review of 50 randomized controlled trials showed that the failure rate of all 5 major ACT’s at day 28 was below 10%; that DHA-P showed better efficacy compared to artesunate-amodiaquine and comparable cure rates to artemether-lumefantrine.

• A census survey retail outlets in 38 districts in Uganda showed high availability of non-artemisinin monotherapies in the private sector and high availability of ACT’s in urban areas and in the public sector. Artemether-lumefantrine was 11times more expensive than sulphadoxine-pyrimethamine.

• There was a clear rank order, in terms of treatment failure, unadjusted for genotyping in the (increasing) direction DHA-P < AL < AS-AQ

• All artemisinin-containing samples assessed for quality in Nigeria showed high levels of impurities and only 18 (72%) of samples compared with the pharmacopoeia requirements.

FINDINGS AND CONCLUSIONS

• The PCR-adjusted cure rate for artemether-lumefantrine deployed under field conditions in Tanzania was high, showing AL is highly effective and well tolerated when used in the context of the HBMM strategy; however, there was a high risk of re-infection, suggesting other intervention methods should be used together with antimalarial drugs.

• Community-based deployment of AL in rural Ethiopia was associated with reduced case- load, decreased transmission and reduced malaria-specific mortality.

• There was good correlation between day 7 plasma concentrations of desethylamodiaquine and lumefantrine in Ugandan children with uncomplicated malaria treated with AS-AQ or A-L.

• There was high efficacy of DHA-P in children with uncomplicated malaria in Burkina Faso; DHA and piperaquine both displayed variable absorption, and the key PK parameters were not different from adults.

• DHA-P showed better efficacy compared to AS-AQ, and comparable cure rates to artemether-lumefantrine and DHA-P is included as an appropriate first-line treatment of uncomplicated malaria worldwide.

• There was high availability of non-artemisinin monotherapies in the private sector and high availability of ACT’s in urban areas and in the public sector; AL was highly expensive in the private sector, suggesting that AL is unaffordable in the private sector.

• DHA-was the most efficacious ACT, in terms of recurrent parasitaemia, when compared to AL and AS-AQ; and the terminal elimination half life of the partner antimalarial should be taken into consideration when comparing ACT’s.

• The presence of sub-standard ACT’s demonstrated in Nigeria; this is a risk to life and may precipitate decreased confidence in ACT’s

From formal presentations

Policy Impact

DHA-P is considered an appropriate alternative ACT for the treatment of uncomplicated malaria but this ACT is not as yet prequalified by WHO. In Uganda, this ACT, which improves adherence and has an excellent post-treatment prophylactic effect, is recommended as alternative/second-line treatment and is available in the private sector but expensive, therefore inaccessible.

From open discussions/debates

It is possible that age-dependent effects upon drug disposition such as absorption and distribution were responsible for the trends in drug exposure demonstrated for the metabolites of the long-acting partner drugs of AS-AQ and AL. single-point Day 7 DEAQ or lumefantrine concentrations may be predictive of drug exposure. The majority of ACT’s in Nigeria is imported but the majority of sub-standard ACT’s have been the ones that are locally produced. The post-treatment prophylactic effect of antimalarials –although beneficial for the individual, has to be balanced against the potential chance of selection for resistant parasites at the population level in areas of high malaria transmission.

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