topnaman | Malaria blog

The world’s most potent antimalarial, artemisinin, is not available to physicians in the United States but a CDC investigational new drug (IND) project is trying to change that. Over 1,000 cases of malaria are imported into the United States every year and many cases present with severe complications as most travelers lack any natural immunity. CDC is making artesunate available for free through its Atlanta headquarters and CDC quarantine stations across the country for the treatment of severe malaria.

Artesunate is a water-soluble derivative of artemisinin which can be delivered orally or intravenously, though the later is the preferred route for severe cases. The standard treatment in the United States for severe malaria is IV quinidine (a quinine derivative) which has more side effects including hypoglycemia, necessitates cardiac monitoring, and is not carried by many hospital formularies. Jones et al. in a recent Cochrane review summarized the benefits of artesunate over quinine for the treatment of severe malaria (an additional ~40% reduction in mortality).

Dr. Phillip Rosenthal describes a case in the NEJM which would benefit from the IND and also provides a broader review of clinical aspects of artemisinin use. He notes artemether, a lipid soluble derivative of artemisinin, can suffer from varied absorption but its important to point out that artemether is invaluable in peripheral health facilities in developing countries where it can be delivered intramuscularly by minimally trained staff.

An estimated 250 million nets at $10 a piece are needed to achieve the current UN goal of 80% coverage in high risk groups - pregnant women and children under five. UN secretary general Ban Ki Moon has raised the bar calling for universal coverage with nets by 2010 as part of his plan to end malaria deaths in Africa by the same target date.

Designing grand plans and setting specific target dates are contentious actions. On one hand it’s a desire to create measurable benchmarks, mobilize the malaria community, and capitalize on the current political interest. On the other side such efforts represent an unachievable, unsustainable push which will provide temporary benefit but no long term control progress as donors and countries fatigue and funding disappears.

Insecticide treated nets (ITNs) are an effective intervention for controlling malaria and its laudable to advocate their widespread use. ITNs though are not a magic bullet and in the absence of local capacity, surveillance systems, long-term funding, and adequate health infrastructure, their distribution will be for naught. Thus, it seems the challenge is to not develop tunnel vision as we speed ahead at 200 miles an hour.

As large scale distributions of insecticide treated bed-nets continue, the selection pressure for insecticide resistance increases. Insecticide resistance, particularly to DDT, helped destroy the malaria control efforts of many countries in the 1960s-70s. Monitoring insecticide resistance is part and parcel of any indoor residual spraying (IRS) program, and is arguably even more important for bed-nets. Currently, bed-nets are made with only one type of insecticide - pyrethroids. Pyrethroids are the only widely used insecticides which are both effective and safe for human contact. Since pyrethroid resistant mosquitoes are known to emerge, large scale resistance is likely inevitable.

The only way to detect insecticide resistance and be able to respond with adequate public health measures is by maintaining strong surveillance programs. In Lancet Infectious Diseases, Kelly-Hope et al. draw upon lessons provided by past campaigns and propose sound recommendations for the future. The authors call for insecticide resistance monitoring systems and outline actual specifics for such plans. In addition to country teams, regional centers are important. By conducting advanced biochemical and molecular assays they can detect emerging resistance and provide crucial lead time to plan for policy change. Many groups pay lip service to the importance of such work but few programs possess a concrete strategy. The costs for a quality surveillance program are minimal but the costs due to widespread insecticide resistant mosquitoes would be catastrophic. We cannot afford to continue flying blind.

Today is world malaria day. It’s a day of advocacy and reflection. We have powerful tools against malaria (IRS, ITNs, combination therapies) and the disease is once again in the public eye. Thus, despite the challenges - which are both numerous and profound, a powerful sense of optimism remains. Let us seize the opportunity.

The answer is two according to Ministry of Health officials as reported by AllAfrica.com. Now, no one (hopefully) believes only two deaths have occurred and yet the figure is presented as fact. This is either a case of imprecise language on the part of a public health official or bad reporting by the news outlet. Either way it points to a larger problem - malaria deaths (or cases) are hard to count and our capacity to do so is very poor. Two recorded deaths could mean two actual deaths (unlikely), or 20, or 200. We have no idea. Since we really don’t know, we should make that clear when we are relaying the information. Unfortunately, as illustrated above, that does not happen. Accurate measurements are essential in public health to deploy and evaluate interventions. Accurate communications are essential in public health to inform stakeholders and maintain trust.

When Melinda Gates ushered the eradication word at a meeting last October, she certainly took the malaria community by surprise. The New York Times examines the reaction to the Gates Foundation’s goal in which responses to eradication have ranged from “audacious” to “foolhardy”. Given the history of malaria eradication, many are skeptical. The previous attempt at eradication from 1955-69, which while having many successes, failed in its ultimate goals. The long-term consequences of the Global Malaria Eradication Program included a lack of malariologists and the dismantling of malaria control infrastructure leading to terrible resurgences in many countries. The WHO malaria chief Dr. Arata Kochi, who has other complaints against the foundation (previously posted here), also dismisses eradication as counterproductive. Supporters, like Sir Richard Feachem who was the first director of the Global Fund, counter we are in a different era with the public exposure, political support, funding, and control tools to make eradication a reality.

With polio not yet eradicated, though tantalizingly close, I wonder if this pronouncement was premature? Regardless, of one’s position on malaria eradication, we should broadly consider how many eradication programs are simultaneously possible or desirable? The eradication debate will continue though one concern of many scientists is the loss of Gates Foundation support to those who do not preach the gospel of eradication. It will be interesting to see how the cards play out.

The KEMRI-Oxford group has published a new map of malaria transmission. This is a terrific accomplishment providing a global picture of falciparum malaria and answers some basic questions: where is malaria a risk and how intense is that risk? Using results from 4,278 surveys, the researchers found approximately 2.37 billion people live in areas at risk of malaria infection of which 1 billion live in areas of unstable or low transmission. Furthermore, areas of high parasite rates (>50%) are largely in sub-Saharan Africa while other malaria endemic areas are largely hypoendemic (<10%).

While mapping transmission is easier than estimating the number of worldwide cases, it is an undertaking fraught with significant obstacles. In the accompanying editor’s summary, Stephen Rogerson duly notes the accuracy of the findings are dependent on the author’s assumptions and the accuracy of the underlying data. Quite honestly, some of the methodology used in the paper is a bit beyond my skills, but most of the assumptions presented seemed very reasonable and the authors are terrific researchers. I think the spatial limits are more likely to be accurate than transmission intensities due to challenges with the input data. Cross sectional surveys are subject to multiple biases including death bias, seasonal bias, and missing asymptomatic infections. Furthermore, as the authors note, the data is not population representative which is a deficiency plaguing the surveillance of most tropical diseases and a crucial challenge to address for effective control.

Regardless of the precise numbers, the larger trends described can support a logical conclusion, one which many people have previously advocated. We can eliminate malaria outside of sub-Saharan Africa as these regions are of low and unstable transmission and yet comprise almost half of the world’s population at risk for malaria. It’s an exciting proposition and a growing possibility.

GlaxoSmithKline pulled Lapdap (chloroproguanil-dapsone) from the market and ended the development of Dacart (Lapdap+artesunate) after phase III trials of the drugs showed significant hemoglobin reductions in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency. Patient’s with G6PD deficiency have weaker red blood cell membranes which can rupture when exposed to oxidative stress caused by certain drugs including the antimalarial primaquine. The sudden hemolysis and loss of hemoglobin can lead to severe anemia which may require blood transfusions. 10-25% of people in sub-Saharan Africa are G6PD deficient because, like the various hemoglobinopathies such as sickle cell, G6PD deficiency protects against severe malaria.

Kenya was the only market where Lapdap was being sold and GSK was developing Dacart with the Medicines for Malaria Venture (MMV), an interesting public private partnership model which seeks to mitigate some of the financial risks associated with drug development (well illustrated in this case). Still, it’s an unfortunate development to lose treatment options, but there were other concerns with these drugs. While Lapdap and Dacart’s toxicity in certain patients are well acknowledged, their cross resistance with another antifolate, sulphadoxine-pyrimethamine (SP), is a significant impediment as well. SP, which also inhibits folic acid synthesis, has been used worldwide for decades and SP resistant strains exist in many places in sub-Saharan Africa. The same molecular mechanisms which confer SP resistance, point mutations in the dhfr and dhps genes, confer Lapdap resistance. Thus, the therapeutic life of Lapdap and Dacart would be compromised in areas with preexisting SP resistance. Research by Dr. Alisa Alker (a former mentor of mine) and others have shown the presence of these mutations in sub-Saharan Africa whose prevalence would have rapidly increased in the face of increased drug pressure. Lapdap and Dacart are gone, but they may have not been the best of options in the first place.

My goal for the blog is to achieve one post every day. Clearly, I’ve missed that mark, blogging while traveling is a trick which might take me some time to master. Until then, my apologies for any lapses in news and comments.

Last week Nature carried a commentary from Mark Grabowsky, malaria manager at the Global Fund (previously mentioned here), as part of a special on malaria. The premise of the special is - now that we (the malaria control community) have money, what do we do? Dr. Grabowsky mentions a few ideas: integrating prevention, rapid treatment, and the need for monitoring systems. The last point should have been bolded in the article. If a priority list were to be made for what we should do next, I would rank it first. Good surveillance doesn’t require a lot of money - what it needs is a fundamental committment to data driven decisions. Quality surveillance is the first and most basic requirement for a successful control effort without which, in Dr. Grabowsky’s words, we are indeed flying blind.

Another key take-home from the article is Dr. Grabowsky considers providing access to prompt treatment a greater challenge than delivering bed-nets. There are numbers to back that assertion and the conclusion is not surprising as the lack of functional health infrastructure (consisting of physical centers, trained staff, and adequate supplies) is a greater impediment to providing treatment than to distributing bed-nets which can often be piggy-backed with other campaigns. Health infrastructure is vital for antimalarial treatment, for preventing overdiagnosis and drug resistance, and is an overall health multiplier. Health development efforts have traditionally shied away from directly investing in this area but the picture is changing - the Global Fund now allows such spending as a portion of a country’s grant. For all the challenges we still face, we are learning lessons and applying them.

Studying health delivery means figuring out which techniques work for getting the interventions to the people who need them the most. It means studying how to scale effective techniques, and studying how we can speed up policy making processes. Sounds simple doesn’t it? Unfortunately, its rarely done and certainly without the scientific rigor we apply to other types of research. Harvard professor Jim Kim refers to an “implementation bottleneck” between what we know and are able to apply. At the recent meeting of the American Association for the Advancement of Science Dr. Kim, formerly head of the WHO’s HIV/AIDs department (which was apparently a controversial tenure), urged the creation of “the science of healthcare delivery”. It’s a message which strongly resonates with me. We can control malaria if we deploy our current tools widely and effectively. First, we need to learn how.