Theory and Reality: A Natural Experiment

Yes, another blog about malaria…deal with it. ***DISCLAIMER***This entry became longer than intended, so please know that going in. There is, however, a story involved, so hopefully it won’t seem as long as it is.

In my previous Malaria 101 posting, I spoke of how Ghana’s new “Strategic Plan for Malaria Control” calls for moving from a presumptive clinical diagnosis to a diagnosis based on laboratory testing or rapid diagnostic test (RDT). In theory, this has tremendous potential to reduce costs for patients and the overall health system; to decrease the likelihood of drug resistance emerging, thereby preserving the efficacy of artemisinin-base combination therapies (ACTs); and to improve the health outcomes for the public by treating patients for the disease that is actually ailing them. That is in theory; in practice (aka: in reality) is another story entirely. To illustrate this, I will detail a natural experiment I was lucky enough to conduct some weeks ago. But first, a little bit more explanation of the malaria diagnostic situation.

When ACTs first came on the scene 5-10 years ago, the malaria community was so happy that there was a highly efficacious, well-tolerated alternative to chloroquine and SP (the two antimalarials in wide use at the time, to which plasmodium falciparum had developed high resistance profiles in several countries), that it’s number one priority became increasing access to ACTs as quickly as possible. In this regard, many countries (including Ghana) made ACTs available over the counter, instead of needing a prescription, and the WHO recommended clinical diagnosis in high burden areas, especially for children under 5. So basically, for the last 5-10 years, if you felt feverish or sick in Ghana, you could pop into your local pharmacy or licensed chemical seller shop*, they could take a look at you, declare that in their opinion it seemed likely that you had malaria, give you a regimen of ACT, transaction completed and you were out the door: not much different than buying advil. But ACTs are not advil. Ibuprofen (advil) fights inflammation. ACTs are anti-infectives that fight living microbes that put up a fight because they don’t want to die. The other issue is price, and the main catch with ACTs is that they are significantly more expensive than chloroquine and SP. Many people can only afford these alternatives, which are actively discouraged by the government but still widely available in the private sector. Alternatively, if a person demands ACT but cannot afford a full regimen, irresponsible drug dispensers have been known to provide less-than-complete doses.

Fast forward to 2010 where several developments have caused the global malaria community and Ghana’s Ministry of Health (MoH) to rethink their treatment strategy. First, there is a growing body of evidence that malaria is being significantly over-diagnosed and, consequently, ACTs over-prescribed. In Ghana, those numbers look something like this: around 90% of patients presenting with fever at both public and private sector health facilities were diagnosed with malaria, whereas the percentage of those febrile patients that actually had malaria (confirmed through laboratory tests) was more around 50%. This is alarming not only because of the vast, unnecessary use of ACTs and other antimalarials, but also because so many sick people are not being treated for the illnesses they have. Second, the first documented cases of resistance to ACTs have been documented along the Thai-Cambodian border. This is troubling both because that is the same hotspot where chloroquine resistance first appeared in the 1950s (before spreading to the rest of the world) and because there is no new antimalarial drug in the pipeline to replace ACTs if they significantly lose efficacy. Third, there is promising evidence of reduced malaria transmission rates in some countries (including Ghana). While this is a very exciting development, it also means that the over-diagnosis that stems from equating all fevers with malaria is even more pronounced. The fourth and final development is the emergence of RDTs on the scene. RDTs for malaria are pretty awesome; they are very easy to administer (a little finger prick, a drop of buffer and voila), they are quick (results in 15 minutes), they are relatively affordable (less than $1) and they are very accurate** (sensitivity and specificity in the high 90th percentiles).

So, faced with these 4 developments, some pioneering countries have decided to change their treatment guidelines. But, as is so often the case, the difference between theory on paper and realities in practice may be massive. The MoH has not rolled this new program out yet, but a little natural experiment I was able to conduct highlights some of the practical issues it might be facing in the private sector. And the story goes like this:

I should first say that one of my number one priorities upon landing in Accra was to secure some RDTs for myself. It took me about a week, but I was eventually able to procure some from the MoH. I had to buy an entire box (30 tests), but like a good boy scout, I was prepared. I kept them under my bed at home.

One day at work, John, PSGH’s good-natured accountant and Jonas, its hard-working on-site handyman, declared that they weren’t feeling very well, and both thought (or in their own words, knew) that they had malaria. Jonas was feverish and achy all over. John, while not feverish, was also achy and had a badly sore throat with bitterness in the back of his mouth: a symptom, he said, that was unique to his bouts of malaria. Rosslyn, PSGH’s head of public health (and a pharmacist like Dennis), immediately took a slip of paper and began writing down some ACTs she recommended, so that Jonas could run out and buy them. Sensing the opportunity, I jumped in and asked if we couldn’t first use RDTs to make sure that they actually had malaria. For a split second you could hear a pin drop, but then they all decided to humor me. I offered to go home with Charles (PSGH's driver) immediately and grab them, but it was already late in the day and John and Jonas both decided that they were fine waiting until first thing in the morning. I felt bad, like I was the reason for them not being treated today, like I was the white man rationing the medication for the Africans. John, always quick with a sarcastic barb, grinned and said, “We will take the test, but I fear we are wasting them, since I have no doubt that it is malaria.” Jonas nodded his agreement. Again, I offered to go home to grab the tests, so we could do them now, but John, seeing the anxiety on my face and sensing the tension, put his arm around my shoulder and said “No worries. Tomorrow, we will see.”

John, PSGH's sly, slick-dressed accountant

Jonas, PSGH's always-smiling handman, with his typical headphones

Tomorrow came quickly, and I was sure to bring the box of RDTs to the office. Jonas was already hard at work when Dennis and I arrived, but we decided to wait for John to do the test. Waiting anxiously for John’s arrival, I opened the box to look through its contents. It was filled with lots of little, individual packages neatly arranged in a space-saving manner. The box contained: single-use sterilized lancets (miniature plastic swords), single-use alcohol swabs, single-use pipettes, the bottle of buffer and the test cards. While it was a little confusing staring at all those little packages, when John arrived, Rosslyn took over - she had actually attended a MoH training session to learn how to correctly administer it – and it was pretty logical. You wipe the tip of the index finger with the alcohol swap, do a little finger prick with the lancet, get a few drops of blood with the pipette, drop two or three into one of the little basins on the card, squeeze two drops of the buffer into the other, and wait 15 minutes for results.

box of malaria RDTs and contents, from left: test card and pipette, buffer, alcohol swap, and sterilized lancet

We administered the tests in Rosslyn’s office, which I currently share with her. Jonas excitedly granted his finger to Rosslyn and watched the proceedings. John, on the other hand, had a decidedly all-knowing air about him, as if this was a meaningless perfunctory task which would only confirm what he had known all along. The “patients” left the room for the interim, as I snuck furtive glances at their test cards on Rosslyn’s desk. RDT results are displayed with 2 clearly-defined lines that would either appear or not on the face of the card. If the “control” line appeared, it meant that you had conducted the test correctly; if it did not, you had to do it over. If the other line appeared, a case of malaria was confirmed. Pretty simple: two lines = yes, one line = no. After a few minutes, the control lines on both of the tests appeared (good), and Rosslyn and I waited anxiously (I saw her sneaking glances, too) for the others. 15 minutes passed, 20 minutes passed, for good measure, we waited a full 30 minutes, but no second line appeared on either test.

RDT card showing negative result, on left are the two basins where the buffer and blood are dropped

When Rosslyn left her office to break the (good) news to them, their immediate response was to question the quality and validity of the test: “Are you sure this thing works?!?” “I’m sure I have it!” Rosslyn successfully parried those concerns by assuring them that the RDT is very accurate and a false negative is extremely rare. The next question, which Rosslyn so eloquently posed to me upon re-entering her office, was more troubling: “OK, now what?” In theory, the answer to the “OK, now what?” question is that the person should now go to the hospital for more tests to determine the identity of the bug that is actually ailing him/her. But I don’t have to reiterate what is wrong with theory. In reality, John had already started taking SP the day before, and Jonas did not want to wait in line at the hospital for more tests, so he did nothing and ended up feeling better in a few days. From a public health standpoint, this little 2-person experiment can provide a lot of insight into challenges facing this new diagnostic policy, especially in the private sector:

1) The public’s perception of what is and is not malaria is incorrect. This might be the consequence of too much of a good thing, where donors, government ministries, NGOs and others have put so much stress on combating malaria that the general public perceives the problem to be worse than it is. Every Ghanaian has grown up knowing and fearing malaria since birth, so when in doubt, they err on the side of malaria. It’s a common sense approach that anyone would do, but it is a real problem that is both very tough to fix and getting bigger, as malaria transmission rates go down.

2) Getting patients and practitioners to use and trust the validity of the RDTs will be a big hurdle. This was evidenced by John and Jonas’ initial reaction to their test results. In the public sector, this is not so much of an issue, but when patients have to actually pay for the RDT with their hard-earned money (instead of just finding a shop that will give them antimalarials without taking an RDT), this is a major challenge. There is also a growing body of evidence showing pharmacists and others dispensing anti-malarials anyways, even in the presence of a negative RDT result. It is not just patients who need to work on their trust issues.

3) Issue 2 in compounded by the profit motive of practitioners. As we know all too well in America, when healthcare is provided by parties with a profit motive, the incentives affecting behavior do not always align with those actions necessary for optimal individual or public health outcomes. Pharmacists in Ghana make good money dispensing anti-malarial drugs. This new policy calls for testing all possible malaria patients with an RDT, and that a good chunk of them (who they would have dispensed anti-malarial drugs to in the past) will come back negative. A negative result will mean that you can either give them something OTC (most likely with a lot smaller profit margin than an ACT) or tell them to go to a hospital for more tests (no further monies coming into your shop). How likely is it that pharmacists and other, less-trained dispensers will turn sick patients away because they need to have more tests done? How likely is it that the patient will actually go wait at the hospital for those tests, when the reason they came into the pharmacy in the first place might have been to avoid those same lines?

4) What did John and Jonas do? John chose to incorrectly self-medicate, while Jonas chose to do nothing. Leaving alone the fact that John managed to procure an antimalarial (SP) which is not supposed to be available anymore outside public hospital (and only used for pregnant women), how likely is it that patients with a negative RDT result will self-medicate, or go from shop to shop until they find one that will give an anti-malarial without conducting an RDT first? The policy is only as strong as its weakest link. And Jonas did nothing. Whether because he did not want to miss work, did not want to wait at the public hospital, could not afford a private clinic, or any other one of myriad reasons, is this outcome any better than anti-malarial over-prescription?

5) This entry is becoming much too long, so the final lesson that can be learned from my little experiment is that laboratory capacity will become even more important when this policy is rolled-out. Two RDTs = two negative results = two more patients that should then go get further testing done. The number of trained laboratory technicians capable of conducting the requisite amount of tests is already much too low in all developing countries. Microscopy takes time, culturing samples takes time, and these health workers are already spread too thinly. Some tests take days or weeks for results: days or weeks in which the patient is still sick. If we really expect patients to obediently wait it out, the MoH should couple this policy roll-out with adequate increased investments in laboratory capacity. Is that happening? All signs on the ground point to no.

So what is my part in all this? I’m trying to secure funding for PSGH to go all over the country and run training programs for all of its member pharmacists in this new policy prior to roll-out. I think that’s enough malaria talk for today. We’re really getting into the weeds on some of this stuff, and I know you’re all very excited! My next couple extries won't be malaria-related at all, so I'll give you all a break for a bit, I promise!

* In Ghana, licensed chemical sellers are able to dispense only over the counter products (including anti-malarials). They are not trained pharmacists and, so, cannot dispense prescription drugs, but they outnumber pharmacists almost 10 to 1.

** There are dozens of malaria RDTs currently marketed worldwide, all with variable quality. Thankfully, the WHO and others partners have begun conducting lot tests to determine the quality of each. The brand I procured from the MoH received very high marks for quality from the WHO lot tests.

More Than You Ever Wanted to Know About Malaria

As promised, here is another work-related blog. I have tried to keep the acronyms to a minimum but found it very difficult. The good news for me is that my work life is starting to get interesting. The bad news for all of you is that my upcoming blogs will invariably have a lot more to do with malaria (control) and a lot less to do with goats and beaches. But seriously, some of this stuff is really interesting (at least to me), and I will try my best to convey it in a way that you will also, hopefully, find it more than soporific. Now, the readership of this blog certainly has varying levels of knowledge about malaria. In an effort to get everyone on the same page, I will do a general overview of the disease and the main interventions currently in use to control it. Once that is taken care of, I can get into the interesting stuff in future entries and keep the explanations to a minimum. For those of you know all of this stuff, bear with me.

Malaria is an infectious parasitic disease endemic to most tropical and sub-tropical countries in the Americas, Asia and Africa. In humans, it is caused by 5 species of a parasite of the genus Plasmodium – falciparum, vivax, ovale, malariae and knowlesi – with falciparum by far the most deadly, as well as the predominant species in sub-Saharan Africa. The parasite is transmitted to humans via a mosquito bite, specifically the female Anopheles mosquito. Once inside humans, the parasites migrate to the liver and begin multiplying inside liver cells. After an incubation period, usually 6-15 days, these cells rupture and the parasites escape into the blood stream and infect red blood cells: killing those and infecting new ones. The most common clinical symptoms of malaria include sustained fever, shivering chills, joint and muscle pain, headache, vomiting, fatigue and dry cough. Severe malaria cases can lead to coma and death. Less common is a malarial infection of the brain, known as cerebral malaria, which can cause permanent cognitive impairments and brain damage, with children being much more vulnerable.

Annually, there are believed to be between 300-500 million cases of malaria each year, killing between 1 and 3 million people: 90% of these deaths occurring in sub-Saharan Africa and the vast majority killing children under 5. Adults die much less often from the disease, especially in endemic areas with "stable malaria" transmission, which I explained in a previous blog. (The large range of disease burden estimates is inherent in high-transmission, resource-poor countries with many constraints to adequate diagnosis. This will be discussed further in future entries, so stay tuned. I know you’re on the edge of your seat.) Malaria is the number one cause of death of children in Africa, and among adults, the lost productivity due to illness is estimated to be 1.3% of GDP. In some high-burden areas, it is estimated that malaria consumes up to ¼ of all household income.

Currently, there are 4 main interventions used to prevent and treat malaria in endemic areas. The first is using insecticide-treated bed nets (referred to as ITNs, LLINs, or other acronyms) to prevent the mosquitoes from biting humans, thereby preventing the transmission of the disease. The rationale behind this is that the Anopheles mosquito likes to bite at night. So, if people can cover their sleeping areas, this can prevent transmission. The current nets last 5 years; after that the insecticide wears off, and they become less effective. Many countries give nets out to pregnant women and children (the most vulnerable population) in the public sector hospitals and clinics for free. Prices vary greatly in the private sector, but in Ghana, you can pick one up in a pharmacy for about $7-$10. Bed nets have been shown to be an extremely cost-effective intervention, and they are now a major part of most national malaria control programs. There are also some NGOs and charities specializing in bed nets that you might have heard of across the pond, most notably Nothing But Nets, which partners with the NBA, and Malaria No More, which runs a very successful program with American Idol called "Idol Gives Back."

The second intervention is called Indoor Residual Spraying (IRS), and it involves going door to door to spray the inside walls of residences with insecticide (yes, sometimes even DDT). The rationale here is that the Anopheles mosquito, in addition to liking to bite at night, also prefers to hang out on the inside walls of homes. If we can make it so that they die every time they land on the wall, then that is one less malaria-carrying mosquito. The IRS only has a 6 month duration and can be fairly expensive, but it has still been shown to be another very cost-effective prevention intervention.

The third tried and true intervention is called Intermittent Preventative Therapy (IPT) during pregnancy. This is where pregnant women are able to take a drug during pregnancy to protect themselves and prevent mother-to-child transmission of malaria. In Ghana, the drug used is called sulfadoxine-pyrimethamine (SP, for short), and is, ideally, given 3 times at different intervals during the 9 month gestation. As children and pregnant women are the most vulnerable populations for malaria infection, this makes inherent sense and has been shown to be very effective.

The final intervention, and the one that I am most involved with in my current capacity, is increasing access to the most effective drugs available: artemisinin-based combination therapies (ACTs). Artemisinin is a drug derived from the plant Artemisia annua, or Chinese wormwood, whose antimalarial properties have been known to Chinese traditional herbalists for centuries. In the last 5-10 years, using ACTs has become the WHO (World Health Organization)-recommended treatment for uncomplicated malaria in all endemic countries due to their high efficacy and tolerability. Unacceptable levels of drug resistance have developed to all of the previous first-line antimalarial treatments, including chloroquine, SP, and artemisinin monotherapy, but using artemisinin in combination (as with ACTs) helps prevent the emergence of resistance, since 2 different drugs with 2 different mechanisms of action are attacking the parasite at once. The challenge with increasing access to ACTs is two-fold: first, over half of all malaria cases are treated in the private sector (mostly in pharmacies and community drug seller shops), and second, the natural extraction of artemisinin is costly, which means that ACTs are quite a bit more expensive than the aforementioned alternatives and out of reach for most people. A lot of this taking place in the private sector means less government control, and in resource-poor developing countries, this means that even though effective treatments are on the shelves, much less effective ones are often given (or a fraction of a regimen of ACT is given), which continues to drive drug resistance.

(Worth mentioning here is an exciting donor-funded project being piloted in 9 countries (including Ghana) called the Affordable Medicines Facility – malaria (AMFm), which will highly subsidize the purchase price of ACTs, hopefully making them as cheap as, if not cheaper than, all other alternatives for the end-user. Much more on this to come in future blogs.)

These challenges are also compounded by the difficulties of adequately diagnosing malaria, where the vast majority of diagnoses (especially in the private sector) are presumptive and symptomatic (euphemistically called clinical diagnosis) rather than confirmed with laboratory tests. This practice is actually recommended by WHO in most high-burden countries, especially for children under 5. However, as the main symptom of malaria is fever, it has becoming common practice to equate all fevers with malaria and treat accordingly. And, not surprisingly, more and more studies have concluded that there is vast over-diagnosis of malaria and over-prescription of antimalarials happening. Combined with this growing evidence base of over-diagnosis, studies showing decreasing transmission rates in some countries (thanks to the interventions above), as well as the development of accurate rapid diagnostic tests (RDTs), have made it feasible to take action in some countries. And Ghana is one of those countries. The 2009 Strategic Plan from Ghana’s National Malaria Control Program (NMCP) calls for moving from clinical diagnosis to laboratory or RDT-confirmed diagnosis. While this is an exciting paradigm shift, indeed, it is one thing to have it on paper, and another thing entirely to roll it out in practice (especially in the private sector).

So there you have it: Malaria 101 brought to you by Scott(y). Don’t say I never gave you anything. As you can see, there are several cost-effective proven interventions in the arsenal, which makes malaria control a very dynamic field to be in. However, challenges remain, especially in relation to leveraging the full potential of the private sector (“leveraging” is business speak for “using to the fullest”), which is why working with pharmacists is an exciting place to be. There will be much more on malaria to come, and you have been adequately warned, so try to contain your enthusiasm. And, to answer your question: no, there is not a vaccine (yet). The farthest one along in the pipeline is British pharmaceutical giant GlaxoSmithKline’s (GSK) RTS,S candidate. It is in phase III clinical trials, but it is at least 3 years away and will most likely only be partially effective (30-60%).

I know that I used the word gestation is this post, so I hope it wasn't too much like a science lesson. And I apologize about the lack of pictures. I’m tired of acronyms, aren’t you?