Malaria Journal - Latest Comments

Survival rate formula assumes stable age structure

Olivier Johan Tavai Briet — 2011-10-18T08:59:03Z

The authors use Davidson's formula (1954) to estimate the survival rate, which assumes that the mosquito population age structure is stable over the period of data collection. Since the data were collected for 10 nights in (only) one month, it is difficult to establish whether the population was approximately stable. If, for instance, the population was growing during the month surveyed, this would lead to underestimation of the survival rate. Even though there is little seasonality of rainfall in the area, the reported low survival rates should be interpreted with caution if there is no evidence that the population was stable.

Reference
Davidson, G. (1954) Estimation of the survival-rate of anopheline mosquitoes in nature. Nature, UK, 174, 792-793.

Correction of typo in additional file

Lisa White — 2011-10-18T08:58:04Z

The equation lambda=R_0*((1/L)+(1/d_treat))*(I_1+I_2)/N should be lambda=R_0*((1/L)+(1/d_in))*(I_1+I_2)/N.

Possible effects of MDA

Dan Wolf Meyrowitsch — 2011-10-18T08:57:00Z

Dear Dr. Walker,

Thank you for the comment to our recent paper, and for the interesting suggestion that ongoing Mass Drug Administration (MDA) with ivermectin applied in the study area for control of lymphatic filariasis might be the course of the observed downward trend in the Anopheles populations.

We acknowledge that ivermectin treatment may have contributed to the observed decline, but find it highly unlikely that a single annual MDA can be the only/major course of this dramatic reduction. First, the vectors were not exposed constantly to ivermectin, as indicated in your comment, but only during a few days each year. Second, the treatment coverage during each MDA was generally well below 80% of the eligible population (i.e. below 60% of the total population). Third, major declines were also observed in the years before the start of MDAs (late 2004). We do find the studies of Kobylinski et al. (2011) on the effect of ivermectin treatment on malaria transmission very interesting, but as also indicated in the paper of Foy et al. (in press) such treatment most likely needs to be given with short intervals to exert a significant effect on the Anopheles population (by the way, both of these papers became available after our paper was submitted to Malaria Journal). However, it is definitely an important issue that needs to be looked further into, and we are currently breaking down our time series of observations in order to analyse for a possible relationship between the timing of MDAs and the decline in Anopheles population.

Finally we would like to emphasize that if MDAs with ivermectin contributed to the decline in Anopheles population there is reason to be worried for the consequences after stop of the lymphatic filariasis or onchocerciasis MDA campaigns. Will the Anopheles vectors return, and will this result in dramatic malaria epidemics with many fatalities?

Best wishes,

Paul Erik Simonsen and Dan Meyrowitsch

A possible explanation for the decline: ivermectin from MDAs for LF

Edward Walker — 2011-08-29T15:12:53Z

This interesting paper reveals a long term, downward trend in relative densities of Anopheles gambiae s.l. and Anopheles funestus in a region of northeastern Tanzania where vector control measures specifically focusing on malaria control have not previously been implemented intensively. The authors conclude that the decline is therefore not due to any specific chemical intervention against the malaria vector populations and must have some other cause.

Ironically, this same research team is studying control of lymphatic filariasis at the same study sites, and have elsewhere documented significant declines in prevalence of microfilaremia, due to Wuchereria bancrofti infection, through well done longitudinal studies. Importantly, that process has been effected by mass distribution of a combination of two drugs: ivermectin and albendazole. Recently, several studies have shown that ivermectin has lethal and sublethal effects, mediated through the blood meal and in the ppb concentration, on Anopheles vectors of malaria in Africa; and also reduces vector survival and therefore vectorial capacity (see references below). It is indeed surprising that the authors here did not attribute the vector population decline to the effects of constant exposure to ivermectin in human blood meals, a decidedly strong chemical intervention whose effects would be predicted to achieve long term population declines such as were observed. That the Culex quinquefasciatus population under study did not decline in the same manner is likely because females of this species have considerably greater host breadth than either Anopheles funestus or Anopheles gambiae and so would have less overall exposure to ivermectin.

References
Fritz ML, Siegert PY, Walker ED, Bayoh MN, Vulule JR, Miller JR. Toxicity of bloodmeals from ivermectin-treated cattle to Anopheles gambiae s.l. Annals Trop Med Parasitol 2009; 103: 539-547.
Kobylinski KC, Sylla M, Chapman PL, Sarr MD, Foy BD. Ivermectin mass drug administration to humans disrupts malaria parasite ransmission in Senegalese villages. American Journal of Tropical Medicine and Hygiene 2011; 85: 3-5.
Foy BD, Kobylinski KC, Marques de Silva I, Rasgon JL, Sylla M. Endectocides for malaria control. Trends in Parasitology 2011; (article in press).

Minor error in Table 1: number of Dd2 rif genes

Alex Rowe — 2011-08-29T15:11:34Z

The number of rif genes in parasite strain Dd2 in Table 1 should read:
rif genes 95
rif pseudogenes 24
rif truncated genes 13
Total 132

Could mosquitoes be dying from malaria?

Frank Ringsted — 2011-08-29T15:11:09Z

The observed decline in malaria transmission and vector population occurs simultaneously with the spread of SP drug resistance. Could it be considered if the changes in the genetic profile of the parasite has become maladaptive for the parasite vector symbiosis, with altered parasite virulence eventually extinguishing the vector?

Erratum Fig 4 Legend

John Hyde — 2011-07-12T16:16:22Z

Erratum: Figure 4 legend. The description of (D) should read:

(D) Mitotic schizont developmentally a little later than (C) showing an apicoplast in the early stages of ramification. The area of intense PfSHMTc fluorescence follows the ‘Y’ shape of the apicoplast closely

Omission from article

Rune Bosselmann — 2011-07-06T22:33:26Z

The authors fail to fully describe the product they are investigating but only state insecticide content for the sides of Permanet 3.0 and not the roof, which is the interesting part of the product as it contains the combination with PBO.

The sides of Permanet 3.0 contain 2.8g/kg and the roof contains 4 g/kg (so almost 50%more) and 25 g/kg PBO. In comparison Permanet 2.0 has about 2g/kg or only half that of the roof of Permanet 3.0.

In the discussion section of the article (p. 18 in the pdf) the authors note that;

"The high dose of deltamethrin alone in the side panels of unwashed PermaNet® 3.0 could explain the significant difference
in mortality of resistant An. gambiae s.s with this net compared to the other treatment arms"

It is a grave omission to not further note that the dose of deltamethrine in the roof of permanet 3.0 is even higher, twice that of Permanet 2 and 50% more than the sides of 3.0 and that this could explain the difference in mortality of resistant An. gambiae s.s with this net compared to the other treatment arms, incl the sides of Permanet 3.0.

This finding is line with the fact that resistance is not a "yes / no" function but a sliding decrease in susceptability that can to an extend (and for while) be countered with an increase in the dose of active. This is nicely demonstrated in the article, also by the better performance of the roof than the sides of Permanet 3.0.

In order to better represent these findings in the conclusion one should better have written, The additive impact of unwashed PermaNet® 3.0 over PermaNet® 2.0 can be explained by the higher dosage of deltamethrin - etc. This would leave out any doubt as to whether the effect of adding PBO to the yarn of the product was in fact demonstrated in the study.

The authors as well as the reviewers of the article should have picked up that the very subject of the study was not properly described and therefore not taking into account when considering and concluding on the data.

On the Potential Pitfalls of Data Mining: Response to Kuemmerle et al. Assessment of global reporting of adverse drug reactions for antimalarials, including artemisinin-based combination therapy, to the WHO Programme for International Drug Monitoring

Ushma Mehta — 2011-06-30T10:56:24Z

The recent scaling up of access to Artemisinin-based Combination Therapies (ACTs), particularly in target populations frequently under-represented in clinical trials (e.g. infants, pregnant women, those with co-morbid HIV/AIDS and or malnutrition) highlights the importance of reporting, collating and analyzing data on adverse drug reactions. The WHO Programme for International Drug Monitoring plays a central role in these activities, disseminating signals of new adverse drug reactions arising from such data as described in the manuscript by Kuemmerle et al.¹

A crucial weakness of this analysis stems from the unclear definition and classification of ACTs. The only ACTs which are included in this report are Artemether-Lumefantrine and Artesunate-Amodiaquine. Despite their widespread use and recommendation by WHO as first-line treatment, the ACTs artesunate plus mefloquine, dihydroartemisinin plus piperaquine and artesunate plus sulfadoxine-pyrimethamine are surprisingly not reported in the database as ACTs.² Could reports associated with these combinations have been misclassified as Artemisinin-based Monotherapies (AMTs)? The paper states (italics added for emphasis):

•"antimalarials reported as concomitant medications were not included in the query".

•"2781 case reports reported more than one anti-malarial evaluated by the national centre as suspected or interacting in causing the ADR. A mean of 2.4 antimalarials were incriminated in this subset of case reports. 2027 of those contained at least one artemisinin derivative and 1992 of these were transmitted by Thailand in the mid-1990s ."

•“Of the AMT reported, Thailand reported 96% of them, but interestingly did not submit any ICSR (individual case safety report) suspecting ACT”

Thus, it appears that in this manuscript and in figure 4 approximately 2000 cases have been misclassified as artemisinin monotherapy (AMT), or mislabeled as artesunate/artemether. Similarly, it appears that the fixed dose combination of dihydroartemisinin-piperaquine was misclassified as dihydroartemisinin AMT. Furthermore, lumefantrine, which is only available in combination with artemether, is also recorded as a “monotherapy” in Figure 4. This highlights the importance of naming the “concomitant” antimalarials.

The omission of concomitantly reported antimalarials may also have led the authors to attribute the adverse reactions to the incorrect antimalarial (italics again added for emphasis):

• "Many of the adverse events reported for ACT or artemisinin-based monotherapy could be potentially serious and involved cardiac, gastrointestinal, nervous and psychiatric systems ".

The majority of reported artesunate “AMTs” ICSRs were more probably attributable to concurrent or sequential treatment of artesunate with with mefloquine.³. The organ systems involved suggest a more likely association with mefloquine, which is well known to exhibit psychiatric, nervous, cardiac and gastrointestinal problems (as does malaria).⁴ Mefloquine plus artesunate has been the recommended treatment in Thailand, where 96% of the reports were generated, since 1995 and was extensively studied in Thailand since the early 1990s.² As the artemisinin derivatives are pivotal in the fight against malaria, it would be problematic if mefloquine-related adverse reactions were to be attributed to artesunate.

To inform assessment of both risks and benefits by policy makers it is important to know what levels of seriousness were given by the national centre for these ICSRs. This was not reported in this manuscript, despite being routinely recorded in the database.

The concerns identified highlight the importance of involving the national centres concerned in the analysis of such data and the potential pitfalls of mining pooled data without considering local practices and conditions from where the data are derived. This applies both in terms of medicine used as well as in terms of capture, management and interpretation of data. Malaria affects all organ systems, therefore adverse drug reactions that mimic the disease itself need to be analysed with great care.

The success of pharmacovigilance programmes depends on healthcare providers being convinced that data is used well enough to justify the time and responsibility they take to submit spontaneous reports of adverse reactions.

Ushma Mehta,
Former Chairperson of Pharmacovigilance Committee, Medicines Control Council, South Africa (March 2008- April 2011) and Independent pharmacovigilance consultant.

Alex Welte
South African Department of Science and Technology/National Research Foundation Centre of Excellence in Epidemiological Modelling and Analysis (SACEMA), Stellenbosch University.

Karen I Barnes,
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town

1. Kuemmerle A, Dodoo ANO, Olsson S, Van Erps J, Burri C, Lalvani PS. Assessment of global reporting of adverse drug reactions for antimalarials including artemisinin-based combination therapy to the WHO programme for International Drug Monitoring. Malaria Journal 2011, 10:57.

2. World Health Organization. Guidelines for the treatment of malaria. Second edition, WHO Press, 2010. Geneva.

3. Wongsrichanalai C, Meshnick SR. Declining artesunate-mefloquine efficacy against falciparum malaria. Emerging infectious diseases 2008; 14(5):716-719.

4. Roche (Pty) Ltd. Lariam® FDA Approved Label. (accessed 12 May 2011)

Correction of the malaria registered cases in Brazil in 2010

Patricia Brasil — 2011-06-15T13:11:41Z

Please, consider correction of the number of malaria registered cases in Brazil in 2010: 343,599 cases and not 3343,599