Efficacy and safety of dihydroartemisinin-piperaquine for treatment of Plasmodium falciparum uncomplicated malaria in adult patients on antiretroviral therapy in Malawi and Mozambique: an open label non-randomized interventional trial.

BACKGROUND: HIV-infected individuals on antiretroviral therapy (ART) require treatment with artemisinin-based combination therapy (ACT) when infected with malaria. Dihydroartemisinin-piperaquine (DPQ) is recommended for treatment of Plasmodium falciparum malaria, but its efficacy and safety has not been evaluated in HIV-infected individuals on ART, among whom drug-drug interactions are expected. Day-42 adequate clinical and parasitological response (ACPR) and incidence of adverse events were assessed in HIV-infected individuals on non-nucleoside reverse transcriptase inhibitor-based ART (efavirenz and nevirapine) with uncomplicated P. falciparum malaria treated with dihydroartemisinin-piperaquine. METHODS: An open label single arm clinical trial was conducted in Malawi (Blantyre and Chikhwawa districts) and Mozambique (Manhiça district) involving patients aged 15-65 years with uncomplicated P. falciparum malaria who were on efavirenz-based or nevirapine-based ART. They received a directly-observed 3-day standard treatment of DPQ and were followed up until day 63 for malaria infection and adverse events. Day-42 PCR-corrected-ACPRs (95% confidence interval [CI]) were calculated for the intention-to-treat (ITT) population. RESULTS: The study enrolled 160 and 61 patients on efavirenz and nevirapine-based ART, with a baseline geometric mean (95% CI) parasite density of 2681 (1964-3661) and 9819 (6606-14,593) parasites/µL, respectively. The day-42 PCR-corrected ACPR (95% CI) was 99.4% (95.6-99.9%) in the efavirenz group and 100% in the nevirapine group. Serious adverse events occurred in 5.0% (8/160) and 3.3% (2/61) of the participants in the efavirenz and nevirapine group, respectively, but none were definitively attributable to DPQ. Cases of prolonged QT interval (> 60 ms from baseline) occurred in 31.2% (48/154) and 13.3% (8/60) of the patients on the efavirenz and nevirapine ART groups, respectively. These were not clinically significant and resolved spontaneously over time. As this study was not designed to compare the efficacy and safety of DPQ in the two ART groups, no formal statistical comparisons were made between the two ART groups. CONCLUSIONS: DPQ was highly efficacious and safe for the treatment of malaria in HIV-infected patients concurrently taking efavirenz- or nevirapine-based ART, despite known pharmacokinetic interactions between dihydroartemisinin-piperaquine and efavirenz- or nevirapine-based ART regimens. Trial registration Pan African Clinical Trials Registry (PACTR): PACTR201311000659400. Registered on 4 October 2013, https://pactr.samrc.ac.za/Search.aspx.

Optimizing the programmatic deployment of the anti-malarials artemether-lumefantrine and dihydroartemisinin-piperaquine using pharmacological modelling.

BACKGROUND: Successful programmatic use of anti-malarials faces challenges that are not covered by standard drug development processes. The development of appropriate pragmatic dosing regimens for low-resource settings or community-based use is not formally regulated, even though these may alter factors which can substantially affect individual patient and population level outcome, such as drug exposure, patient adherence and the spread of drug resistance and can affect a drug's reputation and its eventual therapeutic lifespan. METHODS: An in silico pharmacological model of anti-malarial drug treatment with the pharmacokinetic/pharmacodynamic profiles of artemether-lumefantrine (AM-LF, Coartem®) and dihydroartemisinin-piperaquine (DHA-PPQ, Eurartesim®) was constructed to assess the potential impact of programmatic factors, including regionally optimized, age-based dosing regimens, poor patient adherence, food effects and drug resistance on treatment outcome at population level, and compared both drugs' susceptibility to these factors. RESULTS: Compared with DHA-PPQ, therapeutic effectiveness of AM-LF seems more robust to factors affecting drug exposure, such as age- instead of weight-based dosing or poor adherence. The model highlights the sub-optimally low ratio of DHA:PPQ which, in combination with the narrow therapeutic dose range of PPQ compared to DHA that drives the weight or age cut-offs, leaves DHA at a high risk of under-dosing. CONCLUSION: Pharmacological modelling of real-life scenarios can provide valuable supportive data and highlight modifiable determinants of therapeutic effectiveness that can help optimize the deployment of anti-malarials in control programmes.

Community Participation in Habitat Management and Larviciding for the Control of Malaria Vectors in Southern Malawi.

Larval source management (LSM) could reduce malaria transmission when executed alongside core vector control strategies. Involving communities in LSM could increase intervention coverage, reduce operational costs, and promote sustainability via community buy-in. We assessed the effectiveness of community-led LSM to reduce anopheline larval densities in 26 villages along the perimeter of Majete Wildlife Reserve in southern Malawi. The communities formed LSM committees which coordinated LSM activities in their villages following specialized training. Effectiveness of larviciding by LSM committees was assessed via pre- and post-spray larval sampling. The effect of community-led LSM on anopheline larval densities in intervention villages was assessed via comparisons with densities in non-LSM villages over a period of 14 months. Surveys involving 502 respondents were undertaken in intervention villages to explore community motivation and participation, and factors influencing these outcomes. Larviciding by LSM committees reduced anopheline larval densities in post-spray sampling compared with pre-spray sampling (P < 0.0001). No differences were observed between anopheline larval densities during pre-spray sampling in LSM villages and those in non-LSM villages (P = 0.282). Knowledge about vector biology and control, and someone's role in LSM motivated community participation in the vector control program. Despite reducing anopheline larval densities in LSM villages, the impact of the community-led LSM could not be detected in our study setting because of low mosquito densities after scale-up of core malaria control interventions. Still, the contributions of the intervention in increasing a community's knowledge of malaria, its risk factors, and its control methods highlight potential benefits of the approach.

The efficacy of permethrin-treated bed nets on child mortality and morbidity in western Kenya II. Study design and methods.

This paper describes the study design and methods used in a large community-based, group-randomized, controlled trial of permethrin-treated bed nets (ITNs) in an area with intense, perennial malaria transmission in western Kenya conducted between 1996 and 1999. A multi-disciplinary framework was used to explore the efficacy of ITNs in the reduction of all-cause mortality in children less than five years old, the clinical, entomologic, immunologic, and economic impact of ITNs, the social and behavioral determinants of ITN use, and the use of a geographic information system to allow for spatial analyses of these outcomes. Methodologic difficulties encountered in such large-scale field trials are discussed.

Rapid scale-up of long-lasting insecticide-treated bed nets through integration into the national immunization program during child health week in Togo, 2004.

In December 2004, Togo was the first country to conduct a nationwide free insecticide-treated net (ITN) distribution as part of its National Integrated Child Health Campaign. Community-based cross-sectional surveys were conducted one and nine months post-campaign as part of a multidisciplinary evaluation of the nationwide distribution of ITNs to children 9-59 months of age to evaluate ITN ownership, equity, and use. Our results demonstrated that at one month post-campaign, 93.1% of all eligible children received an ITN. Household ITN ownership and equity increased significantly post-campaign. Nine months post-campaign, 78.6% of households with a child eligible to participate in the campaign retained at least one campaign net. Use by eligible children was 43.5% at one month post-campaign (during the dry season) and 52.9% at nine months post-campaign (during the rainy season). Household ownership of at least one ITN increased from 8.0% pre-campaign to 62.5% one month post-campaign. Together, these findings demonstrate that in this setting, increased household ITN ownership, equity, and retention can be achieved on a national scale through free ITN distribution during an integrated campaign.