Archive for the 'Treatment' Category

More on the not-so-Affordable Medicines Facility for malaria

The evidence just keeps piling up with this new report from Africa Fighting Malaria and a series of papers in Malaria Journal (1, 2, and 3). Not only is the availability and cost falling short of goals as we’ve discussed (here, here, here and here), the patient-centered outcomes which actually matter, are likely far worse. In addition to flaws in the logic of the program and its operations, the report adds a previously undocumented dimension of AFMm failure – leadership. The leaked minutes from its board meeting display an unflattering preoccupation with “reputational risk” for the Global Fund and its donors and a disregard for data that suggests the program may not be working as planned. The report concludes:

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

Stage-specific actions of antimalarial drugs

Key to the theory behind antimalarial treatment is understanding the stage-specific actions of drugs and on a related note their mechanisms of action. The life cycle of malaria is complex and most drugs intervene on limited portions of it. I came across this beautiful figure in a 1962 article from the Bulletin of the World Health Organization (open access!) by Dr Bruce-Chwatt, one of the foremost malariologists of all time and the author of that invaluable malaria bible Essential Malariology. Some of the drugs are outdated but the clear categorization and definitions, separating causal prophylactics from sporonticidal drugs for example which many people confuse, are brilliant. Why does prophylaxis with atovaquone-proguanil continue for 1 week post-return from endemic areas while most other drugs must be continued for 4 weeks?Understanding this diagram tells you why.

 

A needed review on parasite clearance

The parasite clearance curve and, the more commonly used, parasite clearance time is a measure of the reduction of parasite density over time or the time until the patient is parasite free, after beginning treatment. Interest in parasite clearance has peaked as a means to gauge artemisinin resistance (previously discussed here and here) as combination therapies often have few outright failures and other tools to detect early resistance such as in vitro tests and molecular markers are not useful or possible at this time.

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.

New results for intermittent preventative therapy in children

Truly beautiful studies – well designed, well thought, even examined cost and service delivery – were recently conducted for regular, presumptive antimalarial treatment (using SP and amodiaquine) of children in Mali and Burkina Faso in settings where treated bed-nets are already in use (PLoS Medicine – open access!). The intervention was effective at reducing clinical burden – from malaria incidence, the primary target, to secondary endpoints such as anemia, all-cause mortality, and stunting.

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

IPTc Efficacy

85%

75%

65%

Baseline*

Rate

NNT

Rate

NNT

Rate

NNT

1000.0

150.0

0.1

250.0

0.1

350.0

0.2

100.0

15.0

1.2

25.0

1.3

35.0

1.5

10.0

1.5

11.8

2.5

13.3

3.5

15.4

1.0

0.2

117.6

0.3

133.3

0.4

153.8

0.1

0.0

1176.5

0.0

1333.3

0.0

1538.5

*Baseline transmission and rates with the intervention are expressed per 100 persons per season

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.

Lasker award to Dr Tu Youyou for the development of artemisinin therapy

 (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.

ACT subsidies: do they work?

No.

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.

Millions of malaria drugs and dollars down the drain

The Affordable Medicines Facility for malaria (AMFm, previously introduced here) may go down as one of the largest failures in public health history. Subsidizing effective antimalarials (namely artemisinin-combination therapies) for sale through private vendors (largely the wide-spread pharmacy/drug kiosk) is an untested idea for increasing access – yet is backed by more than $225 million in funding at a time when the successful Global Fund is struggling to finance existing commitments.

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


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