1) All cases should be parasitologically confirmed prior to treatment. Presumptive treatment is no longer encouraged. While many areas do not yet have the capacity to do so, the unequivocal recommendation from WHO should help realize universal testing.

2) Dihydroartemisinin+piperaquine has been added as one of five recommended artemisinin combination therapies.

These guidelines are WHO at its best – collecting and synthesizing worldwide evidence in order to provide its members with clear guidance for a complex public health need.

What’s fascinating about the drug is its potential application in other fields. Reported to have anti-viral, anti-inflammatory, and immunosuppressive properties chloroquine has been considered for many uses. Before the days of metronidazole it was a mainstay in the treatment of amoebiasis,  and I believe was used by the famous Dr. Ben Kean in his book M.D. during a fascinating attempt to dislodge the scolex (head) of a tapeworm from the patient’s intestinal wall. In India chloroquine is still used in primary health centers for the treatment of gout and in patients with suspected chikungunya during the recent outbreaks. Let’s see where it goes next.

The article suggests that “For a poor farmer in Cameroon or a poor market woman in Ghana, the difference between 20 cents and $8 is huge” which is true but fails to mention that in many countries ACTs are available free of charge through public and private health facilities. ACTs are already subsidized through national control programs though the extent of their reach could be expanded. I must admit I have my doubts about this plan. First, as Dr. Bernard Nahlen notes in the Times article, there’s scant evidence for a scale-up of this approach. The deputy director of the President’s Malaria Initiative (a solid CDC EIS alumnus – random aside I think CDC involvement is a key reason for PMI’s to date success) is justified in his skepticism. The bulk of data are basic case studies from a few Clinton Foundation pilot projects. Second, even if more rigorous evaluations demonstrate some impact, is it really a desirable way forward?

We need more delivery channels and increasing the availability of ACTs is critical, but it should be done as a component of improving overall case management. The idea of encouraging  indiscriminate pill-popping (even if it is the current scenario) with better drugs probably does not align with most countries health priorities. Additionally, there are also the inherent risks of missing other etiologies of fever and increasing drug pressure. On the other hand, cheap ACTs in drug kiosks may be able to provide quick wins in areas which have seen little progress, but countries should think carefully before embarking on this road. It may be an OK stop gap to stave off some morbidity and mortality in places with non-existent health systems but could sabotage development in the long run.

A follow-up comment I posted on Science magazine’s blog which I think adds some more information:

Going the private route is not new. Global Fund drugs get distributed through private channels in many countries whether it is NGOs or partnerships with industries that have medical facilities. What is newer is the use of drug kiosks but even Cambodia for a few years has been marketing ACTs through private shops – with questionable impact. We’ll see how this effort progresses but it is not likely to help build health systems.

Artemisnin combination therapies (ACTs) are now the first-line treatment in most countries. A benefit of ACTs is their activity against immature (but not fully developed) gametocytes. Theoretically, this will help reduce transmission by decreasing the gametocyte density and the probability a mosquito will ingest sexual stages of the parasite while feeding. However, the number of parasite carriers is more important to the spread of the disease in some areas than in others. In highly endemic settings, the size of the infectious reservoir is not a crucial determinant of transmission intensity. In low transmission settings, eliminating the carriage of gamteocytes is more important. For example, the introduction of ACTs has been associated with decreased malaria transmission in Thailand (Nosten et al. 2000, Lancet; but it is not clear whether the benefit was due to the partially gametocidal nature of ACTs or simply a switch to an efficacious drug).

Following this logic, and hoping to further reduce the number of gametocyte carriers (given the limitation of ACTs against mature forms), a few countries have opted to add primaquine to their treatment regimens. A single dose of primaquine is inexpensive and effective against all stages of gametocytes. While the logic appears sound, we unfortunately have little data regarding the safety and efficacy of doing so. Thus, a research agenda for the primaquine problem was clearly endorsed in the article:

The key operational question now is whether primaquine should be added to artemisinin combination treatments for the treatment of falciparum malaria to reduce further the transmissibility of the treated infection

My interest with primaquine and ACTs began in 2005 when I visited Guyana where single-dose primaquine was included with the artemether-lumefantrine combination. The colorful malaria control director Mr. Indal Rambajan told me WHO officials (it was unclear whether he was referring to country, regional, or headquarters staff) were at the time unhappy with his decision. I’ve since discussed the need for research on the addition of primaquine to ACTs with other malaria workers  and am glad to see it mentioned in print, albeit briefly. The article could have benefited from a more in depth discussion on the challenges in determining  how to answer the aforementioned question.

Measuring the efficacy of primaquine will not be simple because the end-point to determine needs to be malaria incidence. Several clinical trials have compared ACT alone versus ACT plus primaquine in reducing gametocytemia in patients (El-Sayed et al., Shekelage et al., 2007 PLOS One). The data from these trials is helpful, but not conclusive because their results are clinical (whether a patient has gametocytes or not) rather than population-level impact (whether malaria transmission has decreased). The two concepts are related, but not equal and the public health end-point is much harder to determine.  Ideally, I think you would conduct a community intervention trial, where several villages are randomized, and measure changes in malaria incidence at baseline and over-time.

A safety risk exists because primaquine can induce hemolysis in patients with hemoglobinopathies – particularly G6PD deficiency. Testing all patients for G6PD deficiency prior to treatment is not feasible. In addition to the health risk posed to an individual patient, a high frequency of side effects or a few dramatic reactions could erode the public’s confidence in the ACT (as it will not be apparent which component of the treatment was responsible) and the control program at large. Fortunately, it appears the provision of single dose primaquine is relatively benign even in G6PD deficient individuals but we need more data.

Addressing problems such as whether the addition of primaquine to ACT is safe and effective can impact health delivery today. Such research is not easy, on the cutting edge of methodology, or well-funded and that’s too bad since we really need to know. It makes one wonder, “Why haven’t we done this? Which institutions are supposed to provide leadership in identifying and setting research priorities?” Good question.

The latest issue at hand is whether it is now appropriate to pursue a large scale expansion of laboratory confirmation of malaria through the use of rapid diagnostic tests (RDTs) and abandon the presumptive treatment of malaria based on clinical symptoms alone in sub-Saharan Africa. The geographic qualifier in this debate is important – in this region health systems are generally consider weak with little capacity for diagnosis. In addition, given the high burden of malaria, and health worker shortages the standard practice is to treat anyone with suspected malaria which is often simply the presence of fever and leads to a wastage of valuable drugs, promotion of drug resistance, and the under-treatment of other underlying causes of fever.

Of course, both sides support strengthening case management and the use of new tools like RDTs. The counterpoint is not so much a disagreement as it is a caution against rapid implementation. What we don’t know is how much attention scaling RDTs will take (i.e. do we have the capacity without losing focus on other interventions?), how many cases would be miss if presumptive treatment decreased, and when/what context such an effort should be executed. It is a complex scenario. To better understand how to interpret divergent opinions from the lens of program management and strategy, I asked a trusted malaria expert to share his views:

I agree with Blaise and others. However, the problem with the discussion is that Blaise et al. do not sufficiently think through how labour and time intensive the change process will be.  On the other hand, Mike et al. do not sufficiently understand that the process of introducing diagnostics – done properly with all thorough and full coverage of training and quality assurance of products and services – is in itself a health system strengthening activity.

Well, one way to succinctly summarize the debate. What are your thoughts?

In addition the widespread availability of artemisinin monotherapies, near 80% were manufactured after WHO’s intense efforts to convince manufacturers to end production, is particularly worrisome. In many of these areas the bulk of medicines are obtained through private sector channels. Thus, widespread substandard drugs (whether counterfeit or legitimate) will promote clinical failures. These treatment failures have grave implications for increased health burden and increased drug pressure selecting for parasite resistance.

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.

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.