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ศุกร์, 30 มีนาคม 2012

From A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases

Date: Thu 22 Mar 2012
Source: Ars Technica [edited]

Drug resistant malaria takes new ground, raising fears of global spread

In Southeast Asia, drug-resistant falciparum malaria may have evolved
resistance to another frontline therapy and established itself in new
territory in western Thailand, according to the World Health
Organization. The new area in Thailand joins previous hot spots in
Cambodia, Viet Nam, and Myanmar, with the latter being badly equipped
to stanch further spread. Despite containment efforts, the possibility
this strain may spread to Africa, which has the most significant
malaria burden, remains very real.

Twice before, drug resistance has appeared 1st in Southeast Asia then
migrated to Africa (which bears a punishing 90 percent of the world's
malaria burden). Malaria intensity at the Thai-Cambodia border is
comparatively light, but somehow parasites at this location have
managed to evolve a tolerance for some previous frontline drugs,
chloroquine and sulfadoxine-pyrimethamine. From 1980 to 2004, malaria
deaths increased 3-fold to an estimated 1.8 million, according to a
study published in The Lancet. Antimalarial drug resistance was "the
likely driver" according to the study [Murray CJ et al: Global malaria
mortality between 1980 and 2010: a systematic analysis. Lancet. 2012;
379(9814): 413-31;

Artemisinin-based therapies now occupy the frontline of antimalarial
therapy worldwide and have helped control the epidemic. Artemisinin is
usually administered as part of combination therapies (ACTs), where it
is paired with medicines that persist longer in the bloodstream to mop
up residual parasites. By striking at parasites in 2 ways at once, the
probability of mutations providing resistance to both drugs
simultaneously becomes, in theory, infinitesimal.

ACT deployment is massive, with demand likely surpassing 250 million
courses in 2011. The loss of ACTs as an effective therapy would have
huge consequences. "Malaria control completely depends on ACTs," as
Arjen Dondorp put it last October [2011]. Dondorp is Deputy Director
of the Mahidol Oxford Tropical Medicine Research Unit in Thailand.

But the efficacy of artemisinin is weakening, despite its remarkable
prowess. Swift action has been the drug's hallmark, but the parasites
along the Thai-Cambodia border region have slowed the drug's
pharmacodynamic rush. The time to clear parasites has grown longer in
these regions. Worrying signs began appearing in 2002. Initially
suspicion fell on the partner drug, mefloquine. But by 2006,
artemisinin clearly lost a step. Some parasites, found in certain
geographic areas, remained after the standard 3-day treatment. Slowing
clearance times are known harbingers of resistance.

And so it proved: treatment failures continued rising. As a result,
Cambodia switched in 2008 to the most recently approved ACT. That
pairs artemisinin with piperaquine, a chemical relative of
chloroquine. As long as the partner drug continued to work, treatment
would succeed. "Despite the changes observed in parasite sensitivity
to artemisinins," the World Health Organization stated in late 2010,
"the clinical and parasitological efficacy of ACTs is not yet

Initially, piperaquine restored the therapeutic punch of ACTs. But
artemisinin continued to buckle. ACT treatment failures in some areas
rose from just 8 percent in 2008 to 28 percent in 2010. As artemisinin
left behind an increasing fraction of multi-billion parasite
infections (that's how many parasites an infected, symptomatic person
typically carries), pressure grew on the less capable partner drug.
Within the noise of the clinical data on the new ACT came disturbing
sounds of piperaquine cracking, but it was hard to be sure.

WHO worried last November [2011]: "resistance against piperaquine has
far reaching consequences and needs urgent confirmation." Today, WHO
believes that increasing treatment failures are "most probably due to
piperaquine resistance," according to Pascal Ringwald, coordinator of
WHO's Drug Resistance and Containment program.

Saving artemisinin
- ------------------
Substantial efforts have gone into preserving the effectiveness of
this critical malaria fighter. Having twice seen the drug resistance
drama play out, the malaria research community and global health
authorities have tried for a full script rewrite. "We are staying one
step ahead of malaria," said WHO Director General Margaret Chan last
October [2011].

Over the last several years, with funding from the Gates Foundation,
the WHO containment effort drew a noose around the "Tier 1" zones of
confirmed resistance in Cambodia near the Thai border. Cases were
choked off considerably, but resistance has not gone away.

A low but steady number of cases have been reported since late 2009,
despite well-coordinated, intensive screening and treatment of entire
villages, including every man, woman, and child. If the example of
Cambodia is indicative of the limits of intervention, eliminating drug
resistant malaria may not succeed. And unless resistant parasites are
completely eliminated, the eventual spread of resistance is considered

The limited spread and low levels of infection led Melinda Gates to
say "data indicate that the resistance is being contained." But even
as she spoke, the limits of containment were apparent. A new
resistance hot spot is now suspected around Mae Sot in western
Thailand, near the border with Myanmar. It's unclear if Mae Sot
represents a spread of drug-dodging parasites or de novo development.

Thailand was already moving into a nationwide resistance control and
elimination effort, and the country has been highly successful in
suppressing malaria within its borders. However, containment efforts
generally face nearly insurmountable difficulties. People can carry
low levels of malaria parasites and not show symptoms, and these
asymptomatic carriers can still be bitten by mosquitos and support the
transmission of resistant parasites.

Total elimination may require mass population screening and drug
administration, but not all infections can be detected. Microscopy
screening isn't sensitive enough. PCR-based methods are more
discriminating, but they are also more expensive and require technical
skills. And, although it's vastly more sensitive than microscopy, even
PCR can miss very low levels of parasitemia believed capable of
sustaining transmission. Thailand's roll-out of PCR-based surveillance
has evidently been shelved in favor of an expanded microscopy

If finding all the resistant parasites looks daunting, so does killing
them. As researchers recognized in 2009, the contest with drug
resistance has a "last man standing" character. The difficulty of
elimination escalates because "the last few infections to be cleared
are almost all resistant."

The greater the frequency of resistant malaria, the greater the chance
of further evolutionary evasion of drugs. And here, things also look
discouraging. Surveillance continues to discover additional resistance
foci. Mae Sot joins the known hot spots in Cambodia, one in Viet Nam,
and several confirmed and suspected regions in Myanmar. Chinese
scientists in Yunnan province (across Myanmar's northern border) have
published results showing increasing parasite clearance times. This
likely means artemisinin resistance. Confirming resistance is tricky,
as results hinge on the quality of the microscopy, which is unknown.

Resistant malaria in Myanmar is hugely worrisome in multiple respects.
The Tier 1 population of people in areas with drug resistant strains
in Cambodia totaled just 270 000. In Myanmar, Tier 1 encompasses a
population nearly 20 times larger, 4.8 million people. Myanmar's
border areas in the north and east are uncontrolled and coincide with
areas of drug resistance. The central government, now apparently
reforming, has continued to engage in clashes with ethnic-based
militias in those areas. Villages sometimes burn to the ground in the
conflict, while the civilian/combatant distinction essentially does
not exist.

Migration and genetics
- ----------------------
That past spread may provide lessons for the present. Africa once
switched from chloroquine because of resistance originating in
Southeast Asia. But researchers realized the alleles for resistance to
the new drug, sulfadoxine-pyrimethamine (SP), were already sprinkled
across the continent at low frequency. Crucially, there is no fitness
cost for SP resistance, enabling its random spread in the parasite
population. When SP moved to the malaria frontline, resistance grew
very rapidly because the genetic basis was already present. Just add
drug selection pressure and resistant alleles quickly come to dominate
the parasite population.

Resistance to SP is easy to uncover: point mutations in the
dihydrofolate reductase and dihydropteroate synthase genes provide
reliable biomarkers. Artemisinin resistance is far harder to detect.
Instead of comparatively easy assays, a kind of small scale clinical
trial is required in which parasite clearance times must be carefully
measured over a 3-day course of treatment with an adequately sized
cohort of patients.

Continent-wide surveillance is infeasible with such methods. Selective
monitoring would perhaps survey places in Africa like South Sudan
where malaria conditions similar to Cambodia prevail. But South Sudan
may be the most violent place on earth, beset from the outside through
vaguely defined new borders and lacerated within by internecine tribal

The absence of biomarkers not only makes artemisinin resistance hard
to find, it makes distinguishing the spread of existing mutations from
the appearance of new ones impossible. If the blooms of resistance in
Southeast Asia are independent, resistant strains might not need to be
transferred for resistance to develop roots in Africa.

Asked whether elimination of drug resistant malaria was now
impossible, WHO's Pascal Ringwald answered indirectly. "The Prime
Minister of Cambodia has declared elimination of malaria as a priority
and activities will continue…"

Other experts at the Centers for Disease Control and Prevention and
the Gates Foundation also declined to comment on the question.
Ringwald points out that "resistance of chloroquine emerged from 7-8
different foci," when it jumped to Africa. Fewer foci have been
confirmed so far for artemisinin resistance, but the list is growing
and none have been struck off.

[Byline: Robert Fortner]

- --
Communicated by:
ProMED-mail Rapporteur Mary Marshall

[ProMED-mail reported on the reduced sensitivity of _Plasmodium
falciparum_ malaria in 2010 and 2011. Thailand and the border areas to
Myanmar (Burma) and Cambodia have been hot spots for the development
of resistance to antimalarial drugs since the 1960s, where the 1st
reports on chloroquine resistance came from the same area. Later, the
1st reports on mefloquine resistance also came from the border areas
between Thailand and Myanmar and Thailand and Cambodia.

A significant drive of resistance is probably the fake drugs
containing no or subtherapeutical concentrations of the drugs. This
combined with sales of single tablets leads to systematic underdosing
and selection of resistant malaria parasites. In a situation where the
sales of drugs in Myanmar and Cambodia and probably also in Thailand,
the only rational strategy seems to be free distribution of
antimalarial treatment with drugs containing appropriate doses.

A HealthMap/ProMED-mail of the region can be seen at
<http://healthmap.org/r/235J>. - Mod.EP]

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