Evidence to date suggests that the AMFm was pushed forward too far, too fast and with too much money.

Professor Nick White, one of the world’s foremost experts in treating malaria, just published a fantastic review (Malaria Journal – open access!) on the topic. The article presents a great discussion of  measurement issues and common limitations, analyzing by density reduction or time until clearance, the kinetics and trend of results, connections with stage-specific action, and much more. As we’re in the midst of analyzing two years of artesunate+sulphadoxine-pyrimethamine trial data from India’s National Antimalarial Therapeutic Efficacy Monitoring Network, we’re fortunate for the release of the article since examining the parasite clearance in our patients is one of the key concerns.

There is one important caveat here – IPTc is only “effective” where the transmission is quite high. In the communities in Burkina Faso and Mali where the study was conducted transmission was  very intense (3-13 infective mosquito bites per person per month). At medium and low levels of transmission (last two rows of the table) the strategy becomes rather untenable, expending a lot of drug (which wastes money and risks side effects and resistance), for preventing a single case. Caveat to my caveat – the interpretation of rates differences in number needed to treat calculations is not always straightforward though I believe valid in this case.

Table: Number need to treat (NNT) and post-intervention incidence rate across varying baseline transmission and IPTc efficacy

Interestingly, similar to the famous Garki project the reductions in incidence appear to be much greater than reductions in prevalence – likely due to the seasonal nature of the intervention against a high vectorial capacity and thus risk of exposure.  Since the focus here is burden reduction, and not transmission reduction as in Garki, it doesn’t matter though.

]]> http://topnaman.com/treatment/new-results-for-intermittant-preventative-therapy-in-children/feed/ 0 http://topnaman.com/treatment/lasker-award-to-dr-tu-youyou-for-the-development-of-artemisinin-therapy/ http://topnaman.com/treatment/lasker-award-to-dr-tu-youyou-for-the-development-of-artemisinin-therapy/#comments Tue, 13 Sep 2011 06:25:23 +0000 naman http://topnaman.com/?p=1131

 (image credit: Lasker Foundation)

Congratulations to Dr Tu Youyou for her well-deserved Lasker award (considered a precursor to the Nobel prize) in clinical sciences (hat tip: Mariam).

Dr Youyou recieved the honor for her painstaking work screening traditional Chinese herbs for antimalarial properties as part of military project 523 (more on the military and malaria here). The operation isolated Artemisia (also known as sweet wormwood) extracts, refined production, removed toxic elements, and conducted initial human trials which led to the development of the most potent antimalarial drug discovered to date. Artemisinin combination therapies are now the first-line treatment for Plasmodium falciparum in nearly all countries and cure millions of patients each year. The Lasker site includes a fantastic recount (much better than sparse biographies the Nobel committee posts) detailing this great story of scientific rigor applied to a rich knowledge heritage.

According to a recent report by the Evidence to Policy Initiative (funded by the Gates Foundation which in turn also supported the ACT subsidy idea) . The conclusions are no surprise (see here and here for previous discussions on the idea of selling subsidized artemisinin combination therapy in pharmacies). The summary points were:

• Pilots found a rapid rise in ACT availability in private outlets (pharmacies, drug stores, and other retail outlets), as did one national program. Subsidies were associated with reduced consumer prices (i.e., these subsidies were largely passed along the supply chain to the consumer)
• ACT market share increased rapidly in pilots, crowding out other anti-malarials (e.g., CQ, SP, artemisinin monotherapy), but market share did not increase rapidly in national programs
• Pilots found conflicting evidence on ACT use (one trial was positive, one was negative) and national programs found very little change in use
• The available evidence suggests that ACT price subsidies have less impact among poor, remote communities than among wealthier, urban communities

Notice the first two points arose from small pilots, while the latter deal with scaled programs and are more important to note. None of the evaluations addressed patient-facing outcomes, as a good friend would quickly point out, which are likely to be even worse. Thanks to Devi for the link.

First, are decreased private sector costs even passed on to buyers? It’s hard to say in any systematic way, especially past the small trial projects. Daily Nation media from Kenya reports that the first batches to hit drug stands all over the country are going for 1.25  to 6 times the recommended price of Sh40 (US$0.50). Expect similar reports from other countries.

Second, even if the strategy works to lower drug costs in pharmacies – will it have much public health benefit? Access issues will likely persist in rural areas, where the treatments are most needed, as pharmacies are concentrated in urban areas anyways. Among those with access, the majority of people with fever will not actually have malaria and that proportion is declining as control efforts are strengthened. The resultant overuse of drugs will be enormous, other etiologies of fever may go untreated, and increased drug pressure could quicken the spread of resistance. Adherence to the full course of drugs, which are dispensed without much counseling, may be poor. Coupling a system of diagnosis with the subsidized drugs  seems near impossible, and not doing so is irresponsible.

Finally, let’s remember this is not about providing a quality medical service and does nothing to strengthen a country’s health system. The essential strategy of AFMm is to enable people to continue to “self-medicate but now with better drugs”. It is a desperation move, a stop gap at best.

Pro-market groups, such as the Clinton and Gates foundations, who pushed AFMm are showing no signs of stopping – they’ve learned one trick (and not even well) and want to try it out everywhere. In an Indian editorial, Clinton Foundation blindly promotes the idea in a country where it possibly makes the least sense (in India less than 2% of fevers are due to malaria in most areas and the government is making large investments in improving primary care). While the private sector has a role to play in improving malaria care, we should not invest money or energy in risky and unproven approaches towards this end.

PS: Medecins Sans Frontieres commentary about quality concerns with AFMm

Vivax malaria can relapse from liver stages (hypnozoites) adding to patient burden and further transmission. In tropical settings, upwards of 50-80% of patients may relapse within 1-3 months of the primary infection. Treating the dormant liver stages, which are unaffected by standard therapies, requires 14 days of treatment with primaquine. Adherence to therapy is generally regarded as poor – patients already feel better from the main therapy, primaquine has a number of side effects, and daily dosing for two weeks is a long regimen. Explaining the rationale for the therapy is important to ensure adherence but many health workers have little training or time for counseling and, in my experience, often altogether skip it.

Directly observed therapy (DOT) is exactly what it sounds like. It can be resource intensive but is a proven strategy for ensuring complete and effective treatment (particularly in tuberculosis control efforts). The powerhouse Mahidol University tropical diseases group conducted a randomized study of DOT primaquine in Thailand and followed the patients closely over the next three months to look for new infections.

Among those receiving DOT with primaquine the incidence rate of vivax malaria during follow-up was 3.4 cases / 10,000 person-days while in the self-administered group the rate of vivax was 13.5 cases / 10,000 person-days. No serious adverse events were reported. A quick number needed to treat calculation (with some assumptions about risks) reveals that in this setting the use of DOT primaquine in just 11 cases prevented 1 additional case over three months. The authors note the (already impressive) effect of DOT on subsequent P. vivax appearance is likely an underestimate. The self-administered adherence is inflated compared to the real world. Patients are more compliant under trial conditions (they know they are being studied) and a study follow-up visit at day 7 serves as a convenient reminder halfway through the treatment.

Takeuchi et al. also examined risk factors for vivax malaria reappearance and unfortunately devoted the entire discussion to these findings. I think more conversation about the DOT strategy itself – around questions of when, where, and how to use it in program settings – is the true point of interest in this work.