Rural health centres throughout the country are leading the fight against the scourge of drug-resistant malaria. Can international organizations, local health officials and the government unite before the parasite spreads?

Amid the sugar cane plantations and rice paddies of Kampong Speu, the Oral district health centre appears no different from any of its counterparts throughout the country. Yet the work being done here, and at a handful of others selected as “sentinel sites”, has global consequences. It is an integral part of a system at the forefront of the fight against drug-resistant malaria a pervasive problem in Cambodia that has the potential to spread.

Here at the health centre, a team from the National Center for Malaria (CNM) and the district centre’s chief work together to track malaria patients, take samples of their blood, and monitor the effectiveness of the anti-malarial drug cocktail artesunate-mefloquine, or ASMQ for short.

ASMQ was first introduced here in January 2016 and scaled out nationally by the end of December, in response to the increasing failure of the previous combination therapy: dihydroartemisinin-piperaquine (DHA-PIP).

“Before, we used [DHA-PIP], but 50 percent of the patients that used that drug would come back sick,” says health centre chief Chea Him. Since then, he says, his team has been monitoring the effectiveness of ASMQ against the malaria parasite Plasmodium falciparum, considered to be the most virulent strain. The development of resistance in the parasite is, for public health officials at every level, the major concern.

Him receives reports from a network of 47 “village malaria workers”, who administer malaria treatment at the local level. Nationally, some 4,528 such workers are the eyes and ears for monitoring the disease in the most remote and malaria-prone areas of the Kingdom. Villagers showing symptoms of malaria are treated and if need be brought to health centres for treatment. Those found to be infected are closely watched for weeks after their initial treatment.

Without the village workers, the CNM and the World Health Organization are essentially left blind in a high-stakes public health operation launched last year to eliminate P falciparum malaria in Cambodia by 2020. The effort is part of the WHO’s ambitious strategy to eliminate malaria from the Mekong region by 2030.

At a sentinel site like this one in Oral district, blood tests are carried out to monitor the efficacy of current treatments, and some samples are sent on to world-class research institutions such as the Pasteur Institute in Phnom Penh.

“For falciparum, resistance is a problem, because it’s a medical emergency,” explains Pasteur Institute researcher Dr Benoit Witkowski. “You need treatment to work quickly … [because] over 90 percent of malaria deaths are caused by falciparum.”

As such, monitoring resistance is hugely important, but it requires constant oversight and follow-ups.

“It’s not that a treatment is totally ineffectual, but if [resistant] parasites remain alive [in the patient’s blood after treatment], then they multiply and cause a resurgence of the sickness,” he says. This typically happens three weeks after the initial treatment. Then, he explains, when that mosquito bites the patient, it becomes a carrier and will go on to infect others.

Since switching to the ASMQ drug one year ago, the Oral district health centre has treated and tracked 45 cases, none of which have seen a resurgence of malaria.

It is good news for now, but for officials at the World Health Organization in Cambodia, the clock is ticking on when ASMQ will begin to fail.

“Cambodia is always pointed out as the initial place where malarial drug resistance is documented,” says Dr Jean-Olivier Guintran, a medical officer with the WHO’s malaria program. When asked how soon resistance might emerge, head of program Dr Luciano Tuseo pointed to the case of DHA-PIP, which began failing after two years.

“We can expect it to be a matter of months,” he says.

A history of resistance

The history of drug-resistant malaria parasites in Cambodia helps to explain why this is.

In the late 1950s, resistance to chloroquine, the WHO’s principle weapon in their first global malaria eradication campaign, was first detected in Cambodia, and by the late 1970s, it had spread to India and Africa. This caused millions of deaths as public health officials scrambled to deploy alternative treatments.

“Medicines would fail 50 percent of the time, and for children especially, that meant very high mortality,” Tuseo says.

Chloroquine was largely replaced in Southeast Asia with another drug, sulfadoxine-pyrimethamine and then piperaquine, until it too began to fail in the 1980s.

Luckily, in the 1970s, the US Army developed mefloquine, which was successfully deployed to combat malaria; however, by the early ’90s, resistant parasites were once again detected and spread throughout Southeast Asia.

What prevented a repeat of the disaster of chloroquine resistance this time around was the introduction of artemisinin combinations. The artemisinin molecule had been independently developed by Chinese scientist Youyou Tu, for which she later received the 2015 Nobel Prize in medicine.

When Cambodia’s civil war came to an end, the WHO was able to begin monitoring the malaria situation in western Cambodia, historically the breeding ground of drug-resistant parasites, for the first time in decades.

During the Khmer Rouge period, the massive use of only artemisinin supplied by China likely caused resistance to develop, Tuseo says, although resistance to other drugs emerging from Pailin since remains a mystery.

This is the “million dollar” question, Witkowski says. Among the leading hypotheses, he says, is that resistance is driven by the misuse of drugs.

Another theory is that the parasites found here have a high likelihood of genetic mutation, meaning their evolution into a drug-resistant form is more likely than elsewhere.

“It’s also possible that [Southeast] Asian parasites are more capable of mutating [than those found elsewhere] and so the dice throw of finding a more resistant parasite is more likely,” he adds.

Oddly, the relatively low rates of transmission in Southeast Asia actually make drug resistance more likely. Lacking competition from “non-mutant” parasites, the rogue strains are free to evolve.

A history of drug resistant Malaria in Cambodia. Click the arrows to proceed.

The cocktail approach

In response to increasing resistance, the WHO began to recommend artemisinin derivatives, in combinations, such as alongside mefloquine (ie ASMQ), as the frontline treatment.

But yet again, these drugs began to fail, with artemisinin resistance in western Cambodia’s Pailin province suspected as early as 2001 and documented in 2006.

The next drug, DHA-PIP, met the same fate; failure was first detected in Pailin in 2010, then Pursat in 2011, and by 2015, resistance had been documented in eight provinces.

At this point, concern that experts had exhausted the arsenal of available drug combinations was mounting. That’s when they made an important observation.

Scientists such as Witkowski found that as parasites gained resistance to piperaquine (the PIP in the DHA-PIP cocktail) they would lose their resistance to mefloquine (the MQ in ASMQ). In other words, parasites resistant to one molecule would be susceptible to the other, and vice versa.

“That is good news, because if we do rotations of drugs, we have therapeutic options,” Witkowski says.

The breakthrough

Around the same time, researchers studying drug-resistant malaria made a breakthrough: the identification of the genetic marker for artemisinin resistance.

Known as “K13”, this marker suddenly made it much easier to track the spread of parasites resistant to a major component of malaria combination therapies.

Then, in November of last year, the Pasteur Institute’s Malaria Team published the discovery that they were able to do the same for piperaquine resistance. This means that they can quickly identify the type of parasite a patient is infected with.

“This is important to save a patient’s life when there’s no time or capacity to carry out a full blood analysis,” Witkowski says.

Nonetheless, scientists like Witkowski are in a constant battle to stay ahead of the parasite.

“If you want, picture an arrow and a shield of armour,” he explains. “When the arrow gains in perforating capability, you have to improve the shield, and then the arrow becomes stronger, and so on.”

A delicate dance

As the government rolls out a five-year, multimillion-dollar donor-supported plan, coordination between all actors, whether it be scientists, international donors, the WHO or CNM, is critical for success.

The plan has brought with it a near doubling of the number of village malaria workers and the creation of four new sentinel sites. The WHO has also begun testing yet another combination therapy artesunate amodiaquine (ASAQ) in anticipation of the failure of ASMQ.

“Artemisinin resistance is everywhere in Cambodia drug resistant malaria cannot be contained it can only be eliminated,” says Tuseo. Indeed, the WHO’s decision to attempt elimination came after efforts to contain resistant parasites failed. They have spread to Vietnam and Myanmar over the past few years.

“It requires very stringent surveillance to use the best drug possible,” he says. “You can have millions of dollars but nothing will happen. What you need is commitment.”

This process was put in jeopardy when in October 2015 The Post revealed that millions of dollars of aid money from the Global Fund sat idle due to a disagreement with the CNM over declaring travel expenses amid allegations of corruption. During that time, village malaria workers were not being paid, in essence collapsing an integral part of the surveillance of the disease.

In Oral, health centre director Him recalls that the controversy meant his team “did not have a clear picture of the disease at that time”.

That impasse ended one year ago when the Global Fund and the CNM reached a deal. CNM director Huy Rekol, who did not return requests for comment, implied last year that the incident had caused three malaria deaths. But when questioned by reporters on the matter, said “let the past be the past.”

Then last May new revelations about graft at the CNM arose, with the Ministry of Health later acknowledging “irregularities”. Questioned by the National Assembly late last month, Health Minister Mam Bunheng dodged the issue.

For Tuseo, the concern is a repeat of chloroquine resistance in Africa in the 1980s.

Without stringent surveillance, there’s a risk that drug-resistant malaria strains will make it out of the country, eventually reaching Africa where poor infrastructure would obstruct a timely response. For Tuseo, preventing this should motivate the myriad parties involved. “The question needs to be asked, is everyone committed?”

Additional reporting by Kong Meta