Respondent-Driven Sampling on the Thailand-Cambodia Border: Can Malaria Cases be Contained in Mobile Migrant Workers?

Respondent driven sampling methodology, for hidden populations, is an effective strategy to study the migrant populations from Myanmar and Cambodia on the Thailand-Cambodia border, write Amnat Khamsiriwatchara, Piyaporn Wangroongsarb, Julie Thwing, James Eliades, Wichai Satimai, Charles Delacollette and Jaranit Kaewkungwal in the Malaria Journal.

There is substantial population movement across the Thai-Cambodian border that is largely driven by economics. Migrants from both Cambodia and Myanmar settle for varying periods of time in Thailand, often in search of work. The International Organization of Migration reported that Thailand has attracted increasing numbers of migrant workers, mostly from neighbouring countries with over one million registered migrant workers entering the country since 2004.

Migrant workers in Chantaburi on the Thailand side of the Thai - Cambodian border. Pix by WHO/Nat Sumon

Channels for migration, in particular labour migration, are defined by the policy of the destination country, usually in response to the demand of domestic labour markets for foreign workers. When the supply through established channels does not match the demand, irregular migration dynamics develop, and migrants enter illegally and undocumented.

While various government ministries attempt to collect data on migrant workers, they usually have information on the number of registered migrants and those applying for work permits, but little information on the unregistered migrants. The true size of the migrant worker population in Thailand, in particular of irregular migrants, is notoriously difficult to quantify.

Rather than classifying migrant workers as documented or undocumented, the Thailand Ministry of Public Health defines migrants who have been in Thailand for more than six months as M1, and migrants who have been in Thailand for less than six months as M2.

Both M1 and M2 migrants are eligible to receive diagnosis and treatment for malaria free of charge at malaria clinics in border zones. Patients who cross the border for a day to seek treatment at the border clinics are counted among the M2. Migrants in Thailand account for a higher proportion of cases than Thai citizens, especially among the M2 migrants.

Dr. Char Meng Chuor: ‘We Need Community Support to Eliminate Malaria’

CONTAINMENT recently spoke to Dr. Char Meng Chuor the new Director of the National Center for Parasitology, Entomology and Malaria Control (CNM).

Dr. Char Meng Chuor. Pix by WHO/sonny krishnan

One big concern is malaria on the move. How important is the role of village malaria workers or VMWs in the early diagnosis and treatment of mobile migrant workers?

Yes, indeed, malaria on the move among mobile migrant workers is worrying. But first let me clarify one thing on terminology. I like to refer to the village malaria workers as community health workers because they can also work on other diseases at the community-level. At present in each health centers there are only seven to eight full-time health staff as first-line health workers. And as you know most of the villages are far from the health centers. So we need these community health workers to support the work of the health centers.

When Khmer people fall sick, they end to seek treatment from the nearest source available to them. And most often, these community health workers are nearest to them. For that reason they are so important in the fight to contain multi-drug resistant malaria. These community health workers not only carry out early diagnosis and treatment, but they also provide vital information to the mobile migrant workers on how they can protect themselves against malaria.

Counterfeit and substandard anti-malarials are one of the causes for the emergence of MDR-falciparum malaria. What are the efforts to eliminate these counterfeit and substandard drugs sold by the private sector and also enforce the ban on oral artemisinin monotheraphy?

First of all, we have to ensure that communities must have access to genuine medicines. This is essential. We can ban oral monotherapies, but if sick people do not know where to get effective anti-malarials, we will go back to square one. Secondly I need to emphasize the importance of law enforcement. The elimination of malaria by 2025 is a government priority and so it’s important that legislation is in place for the law enforcers to start the crackdown of counterfeit malaria medicines.

But let us not forget that we have to also work with the private sector through partnerships. We are now drafting the strategy for the public-private mix, in terms of malaria. We’re still in the learning process, when it comes to dealing with the private sector. But there’s a lot of donor goodwill to provide technical assistance. The chink in the armour is the private sector because most Khmers when they fall sick go to the pharmacies or drug stores first. We have to convince the private sector on why they need to be good and responsible providers to prevent a public health emergency that could cross borders.

What are the lessons learnt from the Containment Project, and how can these lessons be used as we move from malaria control to elimination?

CNM has been implementing the containment project since January 2009, and we have many lessons to share. The first and most important lesson is that it is possible to reduce malaria incidence in the target zones through good management and implementation of proven strategies in malaria control, such as high-level coverage of long-lasting insecticide treated bed nets, provision of free diagnosis and treatment at the community level, and engagement of the community through malaria education and awareness programs. CNM, through the support of the Bill and Melinda Gates Foundation and the assistance of technical partners such as WHO, Institute Pasteur and Malaria Consortium, and others, has helped us achieve this.

We have also found that, when malaria cases begin to decrease, the role of systematic gathering of health information, including malaria surveillance and response becomes very important. As malaria cases decrease in Cambodia and we are on our path towards elimination, we need to strengthen surveillance systems to capture information on cases up to the village level, and also concentrate on responding to increases in cases through distribution of bed nets and indoor residual spraying.

Another lesson learned is the need to engage and work closely with the private sector in order to be informed of those malaria cases treated by the private sector, in pharmacies and private clinics, and to provide incentives to the private sector to help in the fight against the sale and manufacture of artemisinin monotherapies, as well as fake and substandard drugs.

Also, we need to be sure to have the full support and participation of communities in the fight against artemisinin-resistant malaria, and also move towards elimination. This can be facilitated through wide-ranging media awareness campaigns, community mobilization through local community organizations and distribution of information, education and communication materials, as well as advocacy by involved leaders and authorities.

CONTAINMENT issue No:3

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Responding to Day 3 Falciparum Malaria Positives in Real-Time

Malaria Consortium, with the support of the Bill & Melinda Gates Foundation-funded Containment Project, is pioneering a Day 3 positive alert system in Ta Sanh district, western Cambodia, using mobile phone and web-based technology to facilitate response in real-time. CONTAINMENT’s Sonny Inbaraj reports.

Diagram showing how a text message from the Ta Sanh Health Centre gets disseminated with FrontlineSMS. Source:WHO/Sonny Krishnan

EFFECTIVE containment of multi-drug resistant falciparum malaria depends on timely acquisition of information on new cases, their location and frequency. This is to plan interventions and focus attention on specific locations to prevent an upsurge in transmission.

Response in western Cambodia’s Ta Sanh district involves combining the process of positive diagnoses through microscopy of Day 3 positives at the Ta Sanh health centre from blood slides sent by Village Malaria Workers, to an alert system using mobile phone and web-based technology to help pinpoint potential outbreaks of malaria and target interventions to foci where parasite reservoirs are likely to be present.

The proportion of patients who still carry malaria parasites on the third day of treatment is currently the best measure available of slow parasite clearance and can be used as a warning system for confirmation of artemisinin resistance.

In Ta Sanh, the Village Malaria Workers or VMWs play a crucial role in the early detection and treatment of the killer falciparum malaria. In September 2010 the USAID-funded Cambodia Malaria Prevention and Control Project (MCC), implemented by University Research Co., LLC (URC), trained these VMWs to prepare blood slides from those who tested positive for falciparum malaria from rapid diagnostic tests. They were also trained to carry out a three-day directly observed treatment (DOT) of the Pf cases with the co-formulated ACT dihydroartemisinin – piperaquine.

Chou Khea, a 21-year-old Village Malaria Worker, trained by MCC in Ta Sanh district’s remote Ou Nonoung village tells CONTAINMENT how she carries out DOT.

“Immediately after a villager tests positive for falciparum malaria in a rapid diagnostic test (RDT), I prepare the blood slides. Then I give the drugs, which the villager has to take in front of me,” says Khea.

“On Day 2 and Day 3, I’ll go to the villager’s house and make sure that the drugs are again taken in my presence,” she adds. “After 72 hours from the first intake of the anti-malaria drugs, I’ll be at the villager’s house again to take his or her blood sample for preparing another blood slide.”

Chou Khea then takes the Day Zero and Day 3 slides, together with the used RDT, to the Ta Sanh Health Centre 30-kilometres away from her village.

“I usually take a motor-dop (motorcycle taxi) to the health centre. But most of the motor-dop drivers are reluctant to use the track to health centre in the rainy season because of the slippery mud. Also many of them are scared of the wild animals and land-mines in the area,” she tells CONTAINMENT with concern. “I hope to have my own motorcycle soon, so that I’ll be able to transport the slides and RDTs faster,” she adds with a smile.

A validation, from the database, of the SMS sent from the Ta Sanh Health Centre. Pix WHO/MERG

At the Ta Sanh Health Centre, the Day 3 slides are examined by a microscopist and if asexual malaria parasites are seen they are graded as positive. The microscopist immediately sends out an SMS on a mobile phone, using a dedicated number, to a database indicating the village code and the sex of the patient.

Malaria Consortium pioneered the use of this alert system in Ta Sanh, with support from Cambodia’s National Centre for Parasitology, Entomology and Malaria Control (CNM) and the World Health Organization’s Malaria Containment Project funded by the Bill & Melinda Gates Foundation.

Malaria Consortium’s Information Systems Manager Steve Mellor explains the use of cellular text messaging (SMS) as a viable tool to send alerts and map Day 3 positives in real-time on Google Earth.

“We use FrontlineSMS, an open-source software, that enables users to send and receive text messages with groups of people through mobile phones,” Mellor tells CONTAINMENT.

“FrontlineSMS interfaces with an MS Access database system that was developed to host the SMS data and to provide validation on the data received and to send an automatic reply to the sender containing any validation errors found, or to confirm that the data has been accepted,” he adds.

There are plans to upscale this mobile phone and web-based alert system with InSTEDD, an innovative humanitarian technology NGO, to map all Day Zero cases…

Day 3 positives, in the Access database, mapped in real-time on Google Earth. Pix/Malaria Consortium

In the Access database, a script interfaces with Google Earth and maps out the locations of the Day 3 positives based on the village code. The mapping on Google Earth is essential as it gives a clear visualisation of the terrain and helps CNM, WHO and the USAID-funded Cambodia Malaria Prevention and Control Project (MCC) to plan coordinated interventions in terms of case follow-up on Day Zero and Day 3 and carry out epidemiological and entomological investigations.

“All this happens in real-time and alert text messages are sent out simultaneously to the operational district malaria supervisor, the provincial health department, CNM and the administrators of the database,” Mellor points out.

There are plans to upscale this mobile phone and web-based alert system with InSTEDD, an innovative humanitarian technology NGO, to map all Day Zero cases. Malaria Consortium and CNM are also in direct talks with Mobitel, one of Cambodia’s main telecommunication carriers.

“We are in negotiations with Mobitel for a free number and also free SIM cards to be distributed to health centre staff and village malaria workers,” Mellor reveals. “After all, this is for a public good.”

Besides plans to map all Day Zero cases, Malaria Consortium is also exploring the possibility of sending alert messages in Khmer script.

“This will be a breakthrough and we hope this will help facilitate a quick response mechanism from CNM and other partners,” says Mellor.

Day 3+ves in Ta Sanh, Western Cambodia

Throughout the year for rice cultivation and agricultural activities villagers stay overnight in temporary shelters. Pix WHO/Sonny Krishnan

The drive to Ou Nonoung village in Western Cambodia’s Ta Sanh district is not for the faint-hearted. The almost 45 degree climbs and the steep plunges on the dirt track certainly calls for skilled driving of the 4-WD.

One wrong turn and the vehicle could turn turtle. One wrong detour into the bush and the 4-WD could set off one of the hundreds of unexploded ordinances in the soft dirt – a stark reminder of the war-torn years that almost sent Cambodia back to the Dark Ages.

Ou Nonoung village, in the foothills just below the Cardamom Mountains, lies at the fringe of the forests. In this ’old village’ that goes back to the dark Khmer Rouge-era, villagers have their farms in forest clearings. Throughout the year for rice cultivation and agricultural activities they stay overnight in temporary shelters. These movements in relation to agricultural activities have been identified as risk factors associated with malaria infection.

In these harsh conditions, village malaria workers or VMWs play a crucial role in the early detection and treatment of the killer falciparum malaria. But developments lately have been disturbing.

A warning on the presence of land mines around Ou Nonoung village.

Records from the Ou Nonoung VMW between September 2010 to February 2011 indicate that six villagers had tested positive for falciparum malaria. The results were from rapid diagnostic tests (RDTs). And out of the six Pf positive cases, three still had plasmodium parasites in their blood after a three-day course of treatment with dihydroartemisinin-piperaquine – the artemisinin combination therapy for uncomplicated falciparum malaria currently used along the Thai-Cambodian border.

The Day Three positive cases were verified by microscopy in the Ta Sanh district health center, from blood slides prepared by the VMW from the patients’ blood samples after the three-day course of treatment.

Though the Pf positive cases are relatively small due to active interventions in the Bill & Melinda Gates-funded Containment Project, the presence of Day Three positive patients is a cause for concern.

WHO’s ‘Guidelines for the treatment of malaria’ indicate that: “To eliminate at least 90 percent of the parasitaemia, a three-day course of the artemisinin is required to cover up to three post-treatment asexual cycles of the parasite. This ensures that only about 10 percent of the parasitamia is present for clearance by the partner medicine, thus reducing the potential for development of resistance.” This is the rationale for using dihydroartemisinin and its partner drug piperaquine that is available as a co-formulated tablet.

Host immunity and splenic function are important contributors to parasite clearance after artemisinin treatment. Reduction in herd immunity, perhaps resulting from reduced transmission, could decrease parasite clearance in Cambodia

The question asked is that if symptoms persist 3-14 days after initiation of drug therapy in accordance with the recommended treatment regimen, is that an indication of resistance?

A village malaria worker making a blood slide after doing a rapid diagnostic test. Pix WHO/ Sonny Krishnan

In a recent interview with CONTAINMENT, in Pailin in western Cambodia, Dr. Robert Newman, WHO’s Global Malaria Program director, warns of a worse case scenario.

“The worse case would be the spread of the delay in clearance of the [plasmodium] parasites. Right now we are finding an increase in the percentage of patients who are still positive on Day 3. That will be the hallmark of this problem [of resistance],” said Dr. Newman.

Added Dr. Newman: “If that were to continue to worsen, artemisinins would become less and less efficacious. It would then take longer and longer for patients to clear [plasmodium parasites in their blood], and we could get to the point of truly having failures to ACTs.”

But Dr. Newman clarified that though there is resistance to artemisinins, artemisinin-based combination therapies (ACTs) still remain efficacious. “That is a very important message,” he stressed.

But he issued a stark warning. “If that situation worsens, if were to lose ACTs, and if it spreads to the shores of Africa, we could have a public health catastrophe.”

Acknowledging that there is slow clearance rate in Western Cambodia, Anderson, et al. (2010) ^[1] ask whether slow clearance rate results from parasite, host, or other factors specific to the population in that part of the country.

Writing in the ‘The Journal of Infectious Diseases’, quoting previous studies on the comparison of parasites in Western Cambodia to that in the western part of Thailand along the Thai-Myanmar border, the authors point out that: “ Parasites with slow clearance rate after ACT do not show increased resistance to artemisinin compounds with conventional in vitro testing compared with parasites from western Thailand, which show rapid clearance rate.”

The authors offer several explanations for slow clearance rates.

“Host immunity and splenic function are important contributors to parasite clearance after artemisinin treatment. Reduction in herd immunity, perhaps resulting from reduced transmission, could decrease parasite clearance in Cambodia,” they write.

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^[1] Anderson, T., Nair. S., Nkhoma, S., Williams, J., Imwong, M., Yi, P., Socheat, D., Das, D., Chotivanich,K., Day, N., White,N., Dondorp, A. 2010, “High heritability of malaria parasite clearance rate indicates a genetic basis for Artemisinin resistance in Western Cambodia”, The Journal of Infectious Diseases, vol. 201, no. 9, pp. 1326 – 1330.

The Battle to Contain Resistance

CONTAINMENT recently spoke to Dr. Robert Newman, Director of WHO’s Global Malaria Program, who was on a field visit to Pailin in Western Cambodia.

Dr. Robert Newman, director of WHO's Global Malaria Program. Pix by WHO/Sonny Krishnan

 

There is a long history in malaria control efforts. What’s different now and how has the landscape changed?

Obviously the big issue here right now is the emergence of resistance to artemisinins and this is not just an issue along the Cambodian – Thailand border, but is also a global issue. We rely very heavily on artemisinin-based combination therapies or ACTs and artemisinin is the key ingredient in that combination.

And the stakes are very high because right now we do not have other drugs in the development pipeline that are likely to reach markets before five years, the earliest. And that is an optimistic projection.

So it is really critical that we bring all forces together to try and preserve the efficacy of these valuable medicines.

Here in Western Cambodia we have an extraordinary effort made by the Cambodian National Malaria Control Program and their counterpart program in Thailand to contain the spread of these resistant parasites. The efforts here, I think, have been groundbreaking in their comprehensiveness. Some of the approaches that have been taken are also novel and pioneering.

The Cambodian government has banned the sale of monotherapies. Do you think there should be a similar ban regionally within the Association of Southeast Asian Nations or ASEAN?

Absolutely. I think we all agree now at this point that the use of oral artemisinin monotherapies is probably the single greatest factor for the spread of artemisinin-resistant parasites. In 2007 there was a World Health Assembly resolution that called for a halt in the marketing and use of these compounds.

The worst case would be the spread of the delay in clearance of the [plasmodium] parasites. Right now we are finding an increase in the percentage of patients who are still positive on Day 3. That will be the hallmark of this problem [of resistance]…

While there has been some forward movement in the number of countries that have complied both in terms of shutting down the manufacturer, marketing of these drugs and to some extent in their use, we still have to go some way. This is such an urgent issue. The time to do that is now.

We need all countries, globally – particularly here in the Greater Mekong sub-region and ASEAN to ensure that these dangerous medicines are removed immediately from the market place.

What are the differences between containment and elimination; elimination and eradication?

Containment would mean in this context that we take these resistant parasites and don’t let them spread outside the area where they have been identified. So at this point the confirmed areas are along the Thai-Cambodian border, although there are other areas in the Greater Mekong sub-region where we have suspicion of their emergence.

Elimination would mean that we would actually be able to eliminate all of the parasites. That is a very difficult thing to document. Obviously, if we are able to eliminate these resistant parasites then the risk of their spread is essentially gone.

The term elimination is more generally used to refer to the reduction at the country level of local transmission of malaria to zero. So usually we talk of eliminating malaria at a country level.

Eradication is reserved for the global incidence of malaria going to down to zero. And that’s for all plasmodium species and not just for falciparum. That obviously remains the ultimate public health goal, although I believe that will take 40 or more years to achieve. It would require the development of new transformative tools that we do not have, yet.

What’s the worst case scenario for MDR-falciparum malaria?

The worst case would be the spread of the delay in clearance of the [plasmodium] parasites. Right now we are finding an increase in the percentage of patients who are still positive on Day 3. That will be the hallmark of this problem [of resistance].

If that were to continue to worsen, artemisinins would become less and less efficacious. It would then take longer and longer for patients to clear [plasmodium parasites in their blood], and we could get to the point of truly having failures to ACTs.

Right now we have resistance to artemisinins, but artemisinin-based combination therapies (ACTs) still remain efficacious. That is a very important message.

But if that situation worsens, if were to lose ACTs, and if it spreads to the shores of Africa, we could have a public health catastrophe.

As you know we still have more than 700,000 estimated deaths a year in Africa from malaria. We rely entirely on ACTs for the treatment of falciparum malaria. If we were to lose those medicines in Africa, that would be a catastrophe. This is precisely what the extraordinary efforts in the Containment Project, here, in the Greater Mekong sub-region are trying to prevent.